Methods and systems for glucose regulation

ABSTRACT

Various methods and apparatus for treating a condition associated with impaired glucose regulation in a subject comprising in one embodiment, applying a neural conduction block to a target nerve at a blocking site with the neural conduction block selected to at least partially block nerve pulses. In another embodiment, combinations of down-regulating and or up-regulating with or without pharmaceutical agents are used to treat impaired glucose regulation. In other embodiments, up-regulation or down-regulation of various nerves, such as the vagus and its branches, and the splanchnic is used to modify the production of GLP-1 and GIP, thereby controlling glucose levels. In yet further embodiments, combinations of down-regulating and or up-regulating with or without pharmaceutical agents are used to modify the production of GLP-1 and GIP, to treat impaired glucose regulation.

CROSS-REFERENCE TO OTHER APPLICATIONS

This application claims the benefit of U.S. Ser. No. 61/042,575, filedApr. 4, 2008, which application is incorporated by reference herein.

BACKGROUND OF THE INVENTION

An estimated 18.2 million people in the United States, 6.3 percent ofthe population, have diabetes, a serious, lifelong condition. The majorforms of diabetes are Type 1 and Type 2. Type 1 diabetes is anautoimmune disease resulting in the destruction of the beta cells in thepancreas so that the pancreas then produces little or no insulin. Aperson who has Type 1 diabetes must take insulin daily to live. The mostcommon form of diabetes is Type 2 diabetes. In the United States, about10% of people aged 40 to 59 and 20% of the people 60 years of age andolder have Type 2 diabetes. This disease is the 6^(th) leading cause ofdeath and contributes to development of heart disease, stroke,hypertension, kidney disease and nerve damage. Although severaltreatments are available for diabetes, about 15-32% of the patients failto maintain glycemic control with monotherapy. (Kahn et al, NEJM 355:23(2006)) Type 2 diabetes remains a significant health problem and has acost to the health care system of at least 174 billion dollars. (Dall etal, Diabetes Care 31:1-20 (2008))

Type 2 diabetes is associated with older age, obesity, family history ofdiabetes, previous history of gestational diabetes, physical inactivity,and ethnicity. When Type 2 diabetes is diagnosed, the pancreas isusually producing enough insulin, but for unknown reasons, the bodycannot use the insulin effectively, a condition called insulinresistance. After several years, insulin production decreases, andinsulin must be administered orally or via injection to maintain glucosehomeostasis, as in Type 1 diabetes.

In the early stages of Type 2 Diabetes, therapy consists of diet,exercise and weight loss, later to be followed by various drugs whichcan increase the output of the pancreas or decrease the requirement forinsulin, and finally administration of insulin directly. Pharmaceuticalsfor treatment of diabetes are members of five classes of drugs:sulfonylureas, meglitinides, biguanides, thiazolidinediones, andalpha-glucosidase inhibitors. These five classes of drugs work indifferent ways to lower blood glucose levels. Some increase insulinoutput from the pancreas, some decrease glucose output by affectingliver function. Even with such treatment, some patients do not achieveglycemic control.

Exenatide is the first in a new class of drugs called incretin mimetics,for the treatment of Type 2 diabetes. Exenatide is a synthetic versionof exendin-4, a naturally-occurring hormone that was first isolated fromthe saliva of the lizard known as a Gila monster. Exenatide works tolower blood glucose levels primarily by mimicking the action of GLP-1 toincrease insulin secretion. Because it only has this effect in thepresence of elevated blood glucose levels, it does not tend to increasethe risk of hypoglycemia on its own, although hypoglycemia can occur ifit is taken in conjunction with a sulfonylurea. The primary side effectis nausea, which tends to improve over time. Patients using exenatidehave generally experienced modest weight loss as well as improvedglycemic control.

More recently, a new class of medications called DPP-4 inhibitors hasbeen developed which work by preventing the breakdown of a gut hormone,Glucagon-Like Peptide-1 (GLP-1). GLP-1 reduces blood glucose levels inthe body, but has a half-life ˜2 minutes, and therefore does not workwell when injected as a drug itself. By interfering in the process thatbreaks down GLP-1, DPP-4 inhibitors allow it to remain active in thebody longer, lowering blood glucose levels only when they are elevated.DPP-4 inhibitors do not tend to cause weight gain and tend to have aneutral or positive effect on cholesterol levels. Sitagliptin iscurrently the only DPP-4 inhibitor on the market.

A third category of therapy for Type 2 Diabetics has emerged in the last10 years, and is increasing in popularity for certain patients. Thisinvolves gastric procedures such as various types of gastric bypass, andgastric restrictive techniques. Unexpectedly, these procedures havedemonstrated resolution of Type 2 diabetics (for 75-85% of thepatients), often within 2-3 days of the procedure, and independent ofweight loss. Most patients have been morbidly obese (Body Mass Index,BMI>40), but evolving techniques are allowing the procedures to beapplied to patients with BMI>35, and even over-weight or slightly obesepatients. However, these surgical options are costly and have risks forthe patient both before and after the surgery.

Methods of treating diabetes by upregulating neural activity have beendescribed. Some of these methods for treating diabetes involve directlystimulating pancreatic cells, or parasympathetic/sympathetic tissuewhich directly innervates the pancreas. For example, U.S. Pat. No.5,231,988 to Wernicke discloses application of a low frequencyelectrical signal to the vagus nerve to increase the secretion ofendogenous insulin. U.S. Pat. No. 6,832,114 to Whitehurst describes thedelivery of low frequency signals to at least one parasympathetic tissueinnervating the pancreas to stimulate of pancreatic beta cells toincrease insulin secretion. U.S. Pat. No. 7,167,751 to Whitehurstdescribes methods to relieve endocrine disorders by stimulating thevagus nerve.

Other studies indicate that the role of the vagus nerve with regard toregulation of insulin and blood glucose is not clear. A recent studysuggests that damaging the afferent hepatic vagus nerve can inhibit thedevelopment of insulin resistance in mice treated with dexamethasone.(Bernal-Mizrachi et al., Cell Metabolism, 2007, 5:91). In rats, somestudies indicate that vagotomy induces insulin resistance and in otherstudies, electrical stimulation induces insulin resistance. (Matsuhisaet al, Metabolism 49:11-16 (2000); Peitl et al., Metabolism 54:579(2005)). In another mouse model, hepatic vagotomy suppressed increasesin insulin sensitivity due to peroxisome proliferator-activated receptorexpression. (Uno et al, 2006, Science 312:1656)

Despite the availability of many therapies, Type 2 diabetes remains amajor health issue. Many of the therapies have undesirable side effects,do not achieve adequate glycemic control, or adequate glycemic controlis not maintained. Thus, there remains a need to develop systems andmethods for regulating glucose and/or treating diabetes.

SUMMARY

This disclosure describes methods and systems for treating impairedglucose regulation in a subject. A system comprises a programmable pulsegenerator (neuroregulator) with a lead and at least one electrode, theelectrodes being placed on, or in close proximity to, target nerves ororgans. In some embodiments, the system comprises at least two leads andthe therapy is delivered across each electrode on the leads.

This disclosure is directed to methods and systems for treating acondition associated with impaired glucose regulation such as Type 2diabetes, impaired glucose tolerance, and/or impaired fasting glucose.Patients having impaired glucose tolerance and/or impaired fastingglucose are also referred to as having prediabetes. In an embodiment, amethod comprises treating a condition associated with impaired glucoseregulation in a subject comprising: applying an intermittent neuralsignal to a target nerve at a site with said neural conduction signalselected to down-regulate or up-regulate afferent and/or efferent neuralactivity on the nerve and with neural activity restoring upondiscontinuance of said signal. In some embodiments, the method furthercomprises administering a composition to the subject comprising aneffective amount of an agent that improves glycemic control. In someembodiments, the agent stimulates insulin release, decreases hepaticglucose production, and/or increases insulin sensitivity. In someembodiments, patients are selected that have Type 2 diabetes. In otherembodiments, subjects are patients having impaired glucose toleranceand/or impaired fasting glucose. In some cases, the combination oftreatments may provide for a synergistic effect on Type 2 diabetes orand/or impaired glucose regulation and/or a decrease in the amount ofthe agent required to be effective, thereby minimizing side effects.

In embodiments, a method provides for treating a condition associatedwith impaired glucose regulation in a subject comprising: applying anintermittent electrical signal to a target nerve of the subject havingimpaired glucose regulation, with said electrical signal selected todown-regulate neural activity on the nerve and to restore neuralactivity on the nerve upon discontinuance of said signal. Inembodiments, the electrical signal treatment is selected for frequency,and for on and off times. In some embodiments, the method furthercomprises applying an electrical signal treatment intermittentlymultiple times in a day and over multiple days to a second target nerveor organ, wherein the electrical signal has a frequency selected toupregulate and/or down-regulate activity on the target nerve and has anon time and an off time, wherein the off time is selected to allow atleast a partial recovery of the activity of the target nerve. In someembodiments, the method further comprises administering a composition tothe subject comprising an effective amount of an agent that improvesglycemic control.

In yet other embodiments, methods are directed to modify the amount ofGLP1, GIP, or both. In embodiments, a method of modifying the amount ofGLP1, GIP, or both comprises: applying an first intermittent electricalsignal to a target nerve, with said first electrical signal selected todown-regulate neural activity on the nerve and to restore neuralactivity on the nerve upon discontinuance of said signal, wherein theelectrical signal is selected to modify the amount of GLP1, GIP, orboth. In some embodiments, the method further comprises applying asecond electrical signal treatment intermittently to a second targetnerve or organ, wherein the second electrical signal has a frequencyselected to upregulate activity on the target nerve or organ and torestore neural activity of the second target nerve or to restoreactivity of the target organ to baseline levels. In some embodiments,the method further comprises administering a composition to the subjectcomprising an effective amount of an agent that improves glycemiccontrol.

In another aspect of the disclosure, a system for treating a patientwith impaired glucose regulation is provided. In some embodiments, thesystem comprises: at least two electrodes operably connected to animplantable pulse generator, wherein one of the electrodes is adapted tobe placed on a target nerve; an implantable pulse generator thatcomprises a power module and a programmable therapy delivery module,wherein the programmable therapy delivery module is configured todeliver at least one therapy program comprising an electrical signaltreatment applied intermittently multiple times in a day and overmultiple days to the target nerve, wherein the electrical signal has afrequency selected to downregulate activity on the target nerve and hasan on time and an off time, wherein the off time is selected to allow atleast a partial recovery of the activity of the target nerve; and anexternal component comprising an antenna and a programmable storage andcommunication module, wherein programmable storage and communicationmodule is configured to store the at least one therapy program and tocommunicate the at least one therapy program to the implantable pulsegenerator. In some embodiments, the programmable therapy delivery moduleis configured to deliver a second therapy program comprising anelectrical signal treatment applied intermittently multiple times in aday and over multiple days to a second target nerve or organ, whereinthe electrical signal has a frequency selected to upregulate ordown-regulate activity on the target nerve and has an on time and an offtime, wherein the off time is selected to allow at least a partialrecovery of the activity of the target nerve or organ.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of an alimentary tract (GI tract plusnon-GI organs such as the pancreas and liver) and its relation to vagaland enteric enervation;

FIG. 2 is the view of FIG. 1 showing the application of a blockingelectrode to the alimentary tract;

FIG. 3. is a schematic representation of an implantable systemconfiguration for a gastro-intestinal treatment involving applying anelectrical signal to a vagus nerve;

FIG. 4 is a schematic representation of an exemplary pulse generator(104) and leads (106) comprising electrodes 212 placed on an anteriorand posterior vagus nerve;

FIG. 5 illustrates a schematic representative of another exemplaryembodiment comprising an implantable component comprising an electronicassembly 510 (“hybrid circuit”) and a receiving coil 516; standardconnectors 512 (e.g. IS-1 connectors) for attachment to electrode leads.Two leads are connected to the IS-1 connectors for connection to theimplanted circuit. Both have a tip electrode for placement on a nerve.The patient receives an external controller comprising an antennaconnected to control circuitry. The external control unit can beprogrammed for various signal parameters including options for frequencyselection, pulse amplitude and duty cycle.

FIG. 6 shows recovery of the vagal nerve after application of blockingsignal;

FIG. 7 shows effect of vagal blocking therapy (VBLOC) on percentageexcess weight loss (% EWL) from time of device implant. Data shown areExcess Weight Loss (EWL) % changes (median, interquartile distribution,and 5^(th) and 95^(th) percentiles) with individuals' data plotted forthose beyond those percentiles. Note that while a few individuals didnot lose any weight, 10% patients had >30% EWL at six months, and 25%patients had >25% EWL;

FIG. 8 shows effects of VBLOC on heart rate and blood pressure(mean±SEM);

FIG. 9 shows vagal blocking effects on calorie intake and dietarycomposition. Each visit shows a significant reduction from baseline (allp≦0.01);

FIG. 10 shows effects of VBLOC on satiation and satiety utilizing visualanalogue scales (VAS) expressed as percent change from baseline.Overall, the results show a significant reduction from baseline. A. Timeto satiation (fullness) at meal based on 24 hour recall; B. Hungerbetween meals (satiety) based on 24 hour recall, Decreases representreduced hunger;

FIG. 11 shows effect of pancreatic polypeptide suppression on % EWL at12 wks (mean±SEM, p=0.02).

FIG. 12 shows a typical duty cycle.

DETAILED DESCRIPTION

The following commonly assigned patent and U.S. patent applications areincorporated herein by reference: U.S. Pat. No. 7,167,750 to Knudson etal. issued Jan. 23, 2007; US 2005/0131485 A1 published Jun. 16, 2005, US2005/0038484 A1 published Feb. 17, 2005, US 2004/0172088 A1 publishedSep. 2, 2004, US 2004/0172085 A1 published Sep. 2, 2004, US 2004/0176812A1 published Sep. 9, 2004 and US 2004/0172086 A1 published Sep. 2, 2004.Also incorporated herein by reference is International patentapplication Publication No. WO 2006/023498 A1 published Mar. 2, 2006.

This disclosure includes systems and methods for treating impairedglucose regulation in a subject. In embodiments, a method of treating acondition associated with impaired glucose regulation in a subjectcomprises applying an intermittent electrical signal to a target nerveof the subject, with said electrical signal selected to down-regulateneural activity on the nerve and to restore neural activity on the nerveupon discontinuance of said block. In some embodiments, the target nerveis the vagus nerve. In some embodiments, the site on the target nerve islocated to avoid affecting heart rate such as below the vagalinnervation of the heart. In some embodiments, the electrical signal isselected for frequency, amplitude, pulse width, and timing.

The electrical signal may also be further selected to improve glucoseregulation. Improvement of glucose regulation can be determined by achange in any one of % of HbA1C, fasting glucose, or glucose tolerance.In some embodiments, the method further comprises combining theapplication of an electrical signal treatment with administration of anagent that affects glucose regulation. In some embodiments, theapplication of the electrical signal treatment excludes application ofan electrical signal treatment to other nerves or organs.

As described in Example 1, application of an intermittent electricalsignal treatment in patients provides for excess weight loss with noside effects on blood pressure or heart rate. In addition, applicationof the signal provides for a 30% decrease in calorie intake, an increasein satiation (feeling full), a decrease in satiety (hunger), and adecrease in pancreatic polypeptide. While not meant to limit theinvention, it is expected that a decrease in calorie intake including adecrease in carbohydrates is expected to result in a decrease in glucoseconsumption. In addition, the decrease in pancreatic polypeptideindicates that pancreatic enzymes that participate in digestion willalso be decreased thereby affecting the amount of glucose digested andabsorbed into the system. Any effects of the electrical signaltreatments as described herein on slowed gastric emptying would alsocontribute to a decrease in the amount and rate of glucose absorbed. Adecrease in the amount and rate of blood glucose would lead to adecrease in the amount and rate of insulin production and/oradministration required to control blood glucose.

Pharmaceutical treatments that delay gastric emptying and/or digestionof carbohydrates are known to lower postprandial blood glucoseconcentrations. Patients with delayed gastric emptying also have lesspostprandial glucose excursion. Thus, a treatment includingdownregulation of neural activity that results in a delay of gastricemptying and/or a decrease in carbohydrates consumed likely will resultin lower blood glucose and enhance glucose regulation.

Other aspects of the methods and systems as described herein caninfluence the gut hormone balance to affect one or more of glucoseabsorption, insulin secretion, insulin sensitivity, and endogenousglucose production. Enteroendocrine-derived peptides modulategastrointestinal motility and communicate signals regulating satiety tocentral nervous system centers, initiating and terminating foodingestion. Gut peptides, exemplified by glucagon-like peptide, regulatenutrient absorption and mucosal epithelial integrity, thereby optimizingnutrient absorption. At least 2 gastrointestinal peptides, glucagon-likepeptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide(GIP), function as incretin hormones, potentiating insulin secretion inresponse to enteral nutrient signals.

In non-diabetics, when food enters the mouth, the pancreas initiatesinsulin secretion. As the food progresses into the duodenum, directcontact of the food with the wall of the duodenum produces secretion ofthe incretin hormone glucose-independent insulinotropic peptide (GIP),which among other functions, acts to increase secretion of insulin fromthe pancreas. GIP also promotes secretion of GLP-1 in the jejunum/ileum,which also acts to increase secretion of insulin from the pancreas.GLP-1 secretion in the distal jejunum/ileum shows a peak 15-30 minutesafter food ingestion (GIP/neural pathway mediated), and a second peak90-120 minutes after food ingestion (mediates by direct food contactwith the jejunum/ileum). In Type 2 Diabetics, secretion of GIP isnormal, but its effectiveness is reduced, while the secretion of GLP-1is also reduced relative to normal. For Type 2 Diabetics, modulating thesecretion of gut hormones, such as GLP-1, is way for providing glucoseregulation. Other hormones may also be affected by the methods andsystems as described herein including peptide YY, ghrelin, insulin, andglucagon.

In some aspects of the disclosure, a method and system comprisesmodulating the amount and/or secretion of a polypeptide such asglucagon-like peptide-1 (GLP-1), or glucose-dependent insulinotropicpeptide (GIP) by application of a neural conduction block, or byapplication of neural stimulation, or a combination of both as describedherein in order to facilitate glucose regulation. In other aspects ofthe disclosure, the methods and systems as described herein furthercomprise administration of an agent that affects glucose regulationincluding agents that affect gut hormones. Such administration of anagent can take place in the absence of, or in the presence of neuralblocking and/or neurostimulation.

In some embodiments, a method and system comprises applying anintermittent electrical signal to a target nerve or organ of thesubject, with said electrical signal selected to down-regulate neuralactivity on the nerve and to restore neural activity on the nerve upondiscontinuance of said signal; and applying a second intermittentelectrical signal to a second target nerve or organ of the subject, withsaid electrical signal selected to up-regulate or down-regulate neuralactivity on the nerve and to restore neural activity on the nerve upondiscontinuance of said signal.

In embodiments, the first target nerve is selected from the groupconsisting of the anterior vagus nerve, the hepatic branch of the vagusnerve, the celiac branch of the vagus nerve, and the posterior vagusnerve. In embodiments, the second target nerve can include the celiacbranch of the vagus nerve, nerves of the duodenum, jejunum, small bowel,colon and ileum, and sympathetic nerves enervating the gastrointestinaltract. In some embodiments, the first target organ can include thestomach, esophagus, and liver. In some embodiments, the second targetorgan can include the spleen, duodenum, small bowel, jejunum, colon, orileum. In some embodiments, placement of an electrode on the pancreas isexcluded.

In some embodiments a down regulating signal may be applied to a targetnerve such as the anterior vagus nerve and the upregulating signalapplied to a second target nerve such as the splanchnic or the celiacbranch of the vagus nerve. In some embodiments, the upregulating signalcan be applied to an electrode positioned on an organ such as spleen,duodenum, small bowel, jejunum, colon, or ileum and a downregulatingsignal applied to a vagus nerve. In some embodiments, the upregulatingsignal may be applied in response to detecting the presence of food inthe duodenum or in response to an increase in blood glucose.

A. Description of Vagal Innervation of the Alimentary Tract

FIG. 1 is a schematic illustration of an alimentary tract (GI tract plusnon-GI organs such as the pancreas and gall bladder (pancreas, liver,and gall bladder are considered GI organs), collectively labeled PG) andits relation to vagal and enteric innervation. The lower esophagealsphincter (LES) acts as a gate to pass food into the stomach S and,assuming adequate function of all components, prevent reflux. Thepylorus PV controls passage of chyme from the stomach S into theintestines I (collectively shown in the figures and including the largeintestine or colon and the small intestine including the duodenum,jejunum and ileum). The biochemistry of the contents of the intestines Iis influenced by the pancreas P and gall bladder PG which discharge intothe duodenum. This discharge is illustrated by dotted arrow A.

The vagus nerve VN transmits signals to the stomach S, pylorus PV,pancreas and gall bladder PG directly. Originating in the brain, thereis a common vagus nerve VN in the region of the diaphragm (not shown).In the region of the diaphragm, the vagus VN separates into anterior andposterior components with both acting to innervate the GI tract. InFIGS. 1, and 2, the anterior and posterior vagus nerves are not shownseparately. Instead, the vagus nerve VN is shown schematically toinclude both anterior and posterior nerves. The vagus nerve VN containsboth afferent and efferent components sending signals to and away from,respectively, its innervated organs.

The vagus nerve also includes the hepatic branch and the celiac nerve.The hepatic branch is involved in providing signals regarding glucoseproduction in the liver. The celiac nerve or branch is formed bycontributions from the greater splanchnic and vagus (especially theposterior or right vagus).

In addition to influence from the vagus nerve VN, the GI and alimentarytracts are greatly influenced by the enteric nervous system ENS. Theenteric nervous system ENS is an interconnected network of nerves,receptors and actuators throughout the GI tract and pancreas and gallbladder PG. There are many millions of nerve endings of the entericnervous system ENS in the tissues of the GI organs. For ease ofillustration, the enteric nervous system ENS is illustrated as a lineenveloping the organs innervated by the enteric nervous system ENS. Thevagus nerve VN innervates, at least in part, the enteric nervous systemENS (schematically illustrated by vagal trunk VN3 which represents manyvagus-ENS innervation throughout the gut). Also, receptors in theintestines I connect to the enteric nervous system ENS. Arrow B in thefigures illustrates the influence of duodenal contents on the entericnervous system ENS as a feedback to the secretion function of thepancreas, liver and gall bladder. Specifically, receptors in theintestine I respond to the biochemistry of the intestine contents (whichare chemically modulated by the pancreao-biliary output of Arrow A).This biochemistry includes pH and osmolality.

In FIGS. 1 and 2, vagal trunks VN1, VN2, VN4 and VN6 illustrateschematically the direct vagal innervation of the GI organs of the LES,stomach S, pylorus PV and intestines I. Trunk VN3 illustrates directcommunication between the vagus VN and the ENS. Trunk VN5 illustratesdirect vagal innervation of the pancreas and gall bladder. Entericnerves ENS1-ENS4 represent the multitude of enteric nerves in thestomach S, pylorus PV, pancreas and gall bladder PG and intestines I.

While communicating with the vagus nerve VN, the enteric nervous systemENS can act independently of the vagus and the central nervous system.For example, in patients with a severed vagus nerve (vagotomy—ahistorical procedure for treating ulcers), the enteric nervous systemcan operate the gut. Most enteric nerve cells are not directlyinnervated by the vagus. Gershon, “The Second Brain”, Harper CollinsPublishers, Inc, New York, N.Y. p. 19 (1998).

B. Therapy Delivery Equipment

The disclosure provides systems and devices for treating a conditionassociated with impaired glucose regulation comprising a pulse generatorthat provides signals to modulate neural activity on a target nerve ororgan.

In embodiments, a system comprises at least two electrodes operablyconnected to an implantable pulse generator, wherein one of theelectrodes is adapted to be placed on a target nerve; an implantablepulse generator that comprises a power module and a programmable therapydelivery module, wherein the programmable therapy delivery module isconfigured to deliver at least one therapy program comprising anelectrical signal treatment applied intermittently multiple times in aday and over multiple days to the target nerve, wherein the electricalsignal has a frequency selected to down-regulate and/or upregulateactivity on the target nerve and has an on time and an off time, whereinthe off time is selected to allow at least a partial recovery of theactivity of the target nerve; and an external component comprising anantenna and a programmable storage and communication module, whereinprogrammable storage and communication module is configured to store theat least one therapy program and to communicate the at least one therapyprogram to the implantable pulse generator.

In an embodiment, a system (schematically shown in FIG. 3) for treatingsuch conditions as diabetes or prediabetes includes a pulse generator104, an external mobile charger 101, and two electrical lead assemblies106, 106 a. The pulse generator 104 is adapted for implantation within apatient to be treated. In some embodiments, the pulse generator 104 isimplanted just beneath a skin layer 103.

In some embodiments, the lead assemblies 106, 106 a are electricallyconnected to the circuitry of the pulse generator 104 by conductors 114,114 a. Industry standard connectors 122, 122 a are provided forconnecting the lead assemblies 106, 106 a to the conductors 114, 114 a.As a result, leads 116, 116 a and the pulse generator 104 may beseparately implanted. Also, following implantation, lead 116, 116 a maybe left in place while the originally placed pulse generator 104 isreplaced by a different pulse generator.

The lead assemblies 106, 106 a up-regulate and/or down-regulate nervesof a patient based on the therapy signals provided by the neuroregulator104. In an embodiment, the lead assemblies 106, 106 a include distalelectrodes 212, 212 a, which are placed on one or more nerves or organsof a patient. For example, the electrodes 212, 212 a may be individuallyplaced on the celiac nerve, the vagal nerve, the splanchnic nerve, orsome combination of these, respectively, of a patient. For example, theleads 106, 106 a have distal electrodes 212, 212 a which areindividually placed on the anterior and posterior vagal nerves AVN, PVN,respectively, of a patient, for example, just below the patient'sdiaphragm. Fewer or more electrodes can be placed on or near fewer ormore nerves. In some embodiments, the electrodes are cuff electrodes.

The external mobile charger 101 includes circuitry for communicatingwith the implanted neuroregulator (pulse generator) 104. In someembodiments, the communication is a two-way radiofrequency (RF) signalpath across the skin 103 as indicated by arrows A. Example communicationsignals transmitted between the external charger 101 and theneuroregulator 104 include treatment instructions, patient data, andother signals as will be described herein. Energy or power also can betransmitted from the external charger 101 to the neuroregulator 104 aswill be described herein.

In the example shown, the external charger 101 can communicate with theimplanted neuroregulator 104 via bidirectional telemetry (e.g. viaradiofrequency (RF) signals). The external charger 101 shown in FIG. 3includes a coil 102, which can send and receive RF signals. A similarcoil 105 can be implanted within the patient and coupled to theneuroregulator 104. In an embodiment, the coil 105 is integral with theneuroregulator 104. The coil 105 serves to receive and transmit signalsfrom and to the coil 102 of the external charger 101.

For example, the external charger 101 can encode the information as abit stream by amplitude modulating or frequency modulating an RF carrierwave. The signals transmitted between the coils 102, 105 preferably havea carrier frequency of about 6.78 MHz. For example, during aninformation communication phase, the value of a parameter can betransmitted by toggling a rectification level between half-waverectification and no rectification. In other embodiments, however,higher or lower carrier wave frequencies may be used.

In an embodiment, the neuroregulator 104 communicates with the externalcharger 101 using load shifting (e.g., modification of the load inducedon the external charger 101). This change in the load can be sensed bythe inductively coupled external charger 101. In other embodiments,however, the neuroregulator 104 and external charger 101 can communicateusing other types of signals.

In an embodiment, the neuroregulator 104 receives power to generate thetherapy signals from an implantable power source 151 such as a battery.In a preferred embodiment, the power source 151 is a rechargeablebattery. In some embodiments, the power source 151 can provide power tothe implanted neuroregulator 104 when the external charger 101 is notconnected. In other embodiments, the external charger 101 also can beconfigured to provide for periodic recharging of the internal powersource 151 of the neuroregulator 104. In an alternative embodiment,however, the neuroregulator 104 can entirely depend upon power receivedfrom an external source. For example, the external charger 101 cantransmit power to the neuroregulator 104 via the RF link (e.g., betweencoils 102, 105).

In some embodiments, the neuroregulator 104 initiates the generation andtransmission of therapy signals to the lead assemblies 106, 106 a. In anembodiment, the neuroregulator 104 initiates therapy when powered by theinternal battery 151. In other embodiments, however, the externalcharger 101 triggers the neuroregulator 104 to begin generating therapysignals. After receiving initiation signals from the external charger101, the neuroregulator 104 generates the therapy signals (e.g., pacingsignals) and transmits the therapy signals to the lead assemblies 106,106 a.

In other embodiments, the external charger 101 also can provide theinstructions according to which the therapy signals are generated (e.g.,pulse-width, amplitude, and other such parameters). In some embodiments,the external component comprises an antenna and a programmable storageand communication module. Instructions for one or more therapy programscan be stored in the programmable storage and communication module. In apreferred embodiment, the external charger 101 includes memory in whichseveral predetermined programs/therapy schedules can be stored fortransmission to the neuroregulator 104. The external charger 101 alsocan enable a user to select a program/therapy schedule stored in memoryfor transmission to the neuroregulator 104. In another embodiment, theexternal charger 101 can provide treatment instructions with eachinitiation signal.

Typically, each of the programs/therapy schedules stored on the externalcharger 101 can be adjusted by a physician to suit the individual needsof the patient. For example, a computing device (e.g., a notebookcomputer, a personal computer, etc.) 100 can be communicativelyconnected to the external charger 101. With such a connectionestablished, a physician can use the computing device 107 to programtherapies into the external charger 101 for either storage ortransmission to the neuroregulator 104.

The neuroregulator 104 also may include memory in which treatmentinstructions and/or patient data can be stored. In some embodiments, theneuroregulator comprises a power module and a programmable therapydelivery module. For example, the neuroregulator 104 can store one ormore therapy programs in the programmable therapy delivery moduleindicating what therapy should be delivered to the patient. Theneuroregulator 104 also can store patient data indicating how thepatient utilized the therapy system and/or reacted to the deliveredtherapy.

In some embodiments, the external component and/or the neuroregulator,are programmed with one or more therapy programs. One therapy programmay comprise comprises an electrical signal treatment appliedintermittently multiple times in a day and over multiple days, whereinthe electrical signal has a frequency selected to downregulate activityon the target nerve and has an on time and an off time, wherein the offtime is selected to allow at least a partial recovery of the activity ofthe target nerve. A second therapy program may comprise an electricalsignal treatment applied intermittently multiple times in a day and overmultiple days, wherein the electrical signal has a frequency selected toupregulate or down regulate activity on second target nerve or organ,and has an on time and an off time, wherein the off time is selected toallow at least a partial recovery of the activity of the target nerve.The first and/or second therapy programs may be applied at the sametime, at different times, or at overlapping times. The first and/orsecond therapy programs may be delivered at specific times of the day,and or in response to a signal from a sensor.

Referring to FIG. 3, the circuitry 170 of the external mobile charger101 can be connected to an external coil 102. The coil 102 communicateswith a similar coil 105 implanted within the patient and connected tothe circuitry 150 of the pulse generator 104. Communication between theexternal mobile charger 101 and the pulse generator 104 includestransmission of pacing parameters and other signals as will bedescribed.

Having been programmed by signals from the external mobile charger 101,the pulse generator 104 generates upregulating signals and/ordownregulating signals to the leads 106, 106 a. As will be described,the external mobile charger 101 may have additional functions in that itmay provide for periodic recharging of batteries within the pulsegenerator 104, and also allow record keeping and monitoring.

While an implantable (rechargeable) power source for the pulse generator104 is preferred, an alternative design could utilize an external sourceof power, the power being transmitted to an implanted module via the RFlink (i.e., between coils 102, 105). In this alternative configuration,while powered externally, the source of the specific blocking signalscould originate either in the external power source unit, or in theimplanted module.

The electronic energization package may, if desired, be primarilyexternal to the body. An RF power device can provide the necessaryenergy level. The implanted components could be limited to thelead/electrode assembly, a coil and a DC rectifier. With such anarrangement, pulses programmed with the desired parameters aretransmitted through the skin with an RF carrier, and the signal isthereafter rectified to regenerate a pulsed signal for application asthe stimulus to the vagus nerve to modulate vagal activity. This wouldvirtually eliminate the need for battery changes.

However, the external transmitter must be carried on the person of thepatient, which is inconvenient. Also, detection is more difficult with asimple rectification system, and greater power is required foractivation than if the system were totally implanted. In any event, atotally implanted system is expected to exhibit a relatively longservice lifetime, amounting potentially to several years, because of therelatively small power requirements for most treatment applications.Also, as noted earlier herein, it is possible, although considerablyless desirable, to employ an external pulse generator with leadsextending percutaneously to the implanted nerve electrode set. The majorproblem encountered with the latter technique is the potential forinfection. Its advantage is that the patient can undergo a relativelysimple procedure to allow short term tests to determine whether thecondition associated with excess weight of this particular patient isamenable to successful treatment. If it is, a more permanent implant maybe provided.

According to an embodiment of the present invention, an apparatus isdisclosed for applying an electrical signal to an internal anatomicalfeature of a patient. The apparatus includes at least one electrode forimplantation within the patient and placement at the anatomical feature(e.g., a nerve) for applying the signal to the feature upon applicationof the signal to the electrode. An implantable component is placed inthe patient's body beneath a skin layer and having an implanted circuitconnected to the electrode. The implanted circuit includes an implantedcommunication antenna. An external component has an external circuitwith an external communication antenna for placement above the skin andadapted to be electrically coupled to the implanted antenna across theskin through radiofrequency transmission. The external circuit has aplurality of user interfaces including an information interface forproviding information to a user and an input interface for receivinginputs from the user.

With reference to FIG. 4, a device is shown for application of a signalto a nerve. A stomach S is shown schematically for the purpose offacilitating an understanding of applying a vagal nerve modulatingsignal. In FIG. 4, the stomach S is shown with a collapsed fundus Fwhich is deflated due to fasting. In practice, the fundus F can bereduced in size and volume (as shown in FIG. 4) or expanded. Theesophagus E passes through the diaphragm D at an opening or hiatus H. Inthe region where the esophagus E passes through the diaphragm D, trunksof the vagal nerve (illustrated as the anterior vagus nerve AVN andposterior vagus nerve PVN) are disposed on opposite sides of theesophagus E. It will be appreciated that the precise location of theanterior and posterior vagus nerves AVN, PVN relative to one another andto the esophagus E are subject to a wide degree of variation within apatient population. However, for most patients, the anterior andposterior vagus nerves AVN, PVN are in close proximity to the esophagusE at the hiatus H where the esophagus E passes through the diaphragm D.

The anterior and posterior vagus nerves AVN, PVN divide into a pluralityof trunks that innervate the stomach directly and via the entericnervous system and may include portions of the nerves which may proceedto other organs such as the pancreas, gallbladder and intestines.Commonly, the anterior and posterior vagus nerves AVN, PVN are still inclose proximity to the esophagus E and stomach (and not yet extensivelybranched out) at the region of the junction of the esophagus E andstomach S.

In the region of the hiatus H, there is a transition from esophagealtissue to gastric tissue. This region is referred to as the Z-line(labeled “Z” in the Figures). Above the Z-line, the tissue of theesophagus is thin and fragile. Below the Z-line, the tissue of theesophagus E and stomach S are substantially thickened and more vascular.Within a patient population, the Z-line is in the general region of thelower esophageal sphincter. This location may be slightly above,slightly below or at the location of the hiatus H.

Another embodiment of a device useful in treating a condition associatedwith impaired glucose regulation as described herein is shown in FIG. 5.With reference to FIG. 5, a device comprises an implantable componentcomprising an electronic assembly 510 (“hybrid circuit”) and a receivingcoil 516; standard connectors 512 (e.g. IS-1 connectors) for attachmentto electrode leads. Two leads are connected to the IS-1 connectors forconnection to the implanted circuit. Both have a tip electrode forplacement on a nerve. Set screws are shown in 514 and allow foradjustment of the placement of the electrodes. In some embodiments, amarker 513 to indicate the posterior or anterior lead is provided.Suture tabs 511 are provided to provide for implantation at a suitablesite. In some embodiments, strain relief 515 is provided. The patientreceives an external controller comprising an antenna connected tocontrol circuitry. The external control unit can be programmed forvarious signal parameters including options for frequency selection,pulse amplitude and duty cycle.

In an embodiment, the nerves AVN, PVN are indirectly stimulated bypassing electrical signals through the tissue surrounding the nerves. Insome embodiments, the electrodes are bipolar pairs (ie. alternatinganode and cathode electrodes). In some embodiments, a plurality ofelectrodes may be placed overlying the anterior and/or posterior vagusnerves AVN, PVN. As a result, energizing the plurality of electrodeswill result in application of a signal to the anterior and posteriorvagus nerves AVN, PVN and/or their branches. In some therapeuticapplications, some of the electrodes may be connected to a blockingelectrical signal source (with a blocking frequency and other parametersas described below) and other electrodes may apply an upregulatingsignal. Of course, only a single array of electrodes could be used withall electrodes connected to a blocking or a downregulating signal. Insome therapeutic applications, some of the electrodes may be connectedto an up-regulating electrical signal source (with a suitable frequencyand other parameters as described below).

The electrical connection of the electrodes to an pulse generator may beas previously described by having a leads (eg. 106, 106 a) connectingthe electrodes directly to an implantable pulse generator (eg. 104).Alternatively and as previously described, electrodes may be connectedto an implanted antenna for receiving a signal to energize theelectrodes.

Two paired electrodes may connect to a pulse generator for bi-polarsignal. In other embodiments, a portion of the vagus nerve VN isdissected away from the esophagus E. An electrode is placed between thenerve VN and the esophagus E. Another electrode is placed overlying thevagus nerve VN on a side of the nerve opposite the first electrode andwith electrodes axially aligned (i.e., directly across from oneanother). Not shown for ease of illustration, the electrodes may becarried on a common carrier (e.g., a PTFE or silicone cuff) surroundingthe nerve VN. Other possible placements of electrodes are describedherein US 2005/0131485 published Jun. 16, 2005, which patent publicationis hereby incorporated by reference.

While any of the foregoing electrodes could be flat metal pads (e.g.,platinum), the electrodes can be configured for various purposes. In anembodiment, an electrode is carried on a patch. In other embodiments,the electrode is segmented into two portions both connected to a commonlead and both connected to a common patch. In some embodiments, eachelectrode is connected to a lead and placed to deliver a therapy fromone electrode to another. A flexible patch permits articulation of theportions of the electrodes to relieve stresses on the nerve VN.

Neuroregulator (Pulse Generator)

The neuroregulator (pulse generator) generates electrical signals in theform of electrical pulses according to a programmed regimen. Inembodiments, a blocking signal is applied as described herein.

The pulse generator utilizes a conventional microprocessor and otherstandard electrical and electronic components, and communicates with anexternal programmer and/or monitor by asynchronous serial communicationfor controlling or indicating states of the device. Passwords,handshakes and parity checks are employed for data integrity. The pulsegenerator also includes means for conserving energy, which is importantin any battery operated device and especially so where the device isimplanted for medical treatment of a disorder, and means for providingvarious safety functions such as preventing accidental reset of thedevice.

Features may be incorporated into the pulse generator for purposes ofthe safety and comfort of the patient. In some embodiments, thepatient's comfort would be enhanced by ramping the application of thesignal up during the first two seconds. The device may also have aclamping circuit to limit the maximum voltage (14 volts for example)deliverable to the vagus nerve, to prevent nerve damage. An additionalsafety function may be provided by implementing the device to ceasesignal application in response to manual deactivation through techniquesand means similar to those described above for manual activation. Inthis way, the patient may interrupt the signal application if for anyreason it suddenly becomes intolerable.

The intermittent aspect of the electrical signal treatment resides inapplying the signal according to a prescribed duty cycle. The pulsesignal is programmed to have a predetermined on-time in which a train orseries of electrical pulses of preset parameters is applied to the vagusbranches, followed by a predetermined off-time. Nevertheless, continuousapplication of the electrical pulse signal may also be effective. Insome embodiments, the predetermined on time and off time is programmedto allow for at least partial recovery of the nerve to a state of nondown or up regulation.

Pulse generators, one supplying the right vagus and the other the leftvagus to provide the bilateral upregulation and/or downregulation may beused. Use of implanted pulse generator for performing the method of theinvention is preferred, but treatment may conceivably be administeredusing external equipment on an outpatient basis, albeit only somewhatless confining than complete hospitalization. Implantation of one ormore pulse generators, of course, allows the patient to be completelyambulatory, so that normal daily routine activities including on the jobperformance is unaffected.

In some embodiments, signals can be applied at a portion of the nervoussystem remote from the vagus nerve such as at or near the stomach wall,for indirect regulation of the vagus nerve in the vicinity of thesub-diaphragmatic location. Here, at least one pulse generator isimplanted together with one or more electrodes subsequently operativelycoupled to the pulse generator via leads for generating and applying theelectrical signal internally to a portion of the patient's nervoussystem to provide indirect blocking, down regulation, or up-regulationof the vagus nerve in the vicinity of the desired location.Alternatively, the electrical signal may be applied non-invasively to aportion of the patient's nervous system for indirect application to anerve or organ at a sub-diaphragmatic location.

The pulse generator may be programmed with programming wand and apersonal computer using suitable programming software developedaccording to the programming needs and signal parameters which have beendescribed herein. The intention, of course, is to permit noninvasivecommunication with the electronics package after the latter isimplanted, for both monitoring and programming functions. Beyond theessential functions, the programming software should be structured toprovide straightforward, menu-driven operation, HELP functions, prompts,and messages to facilitate simple and rapid programming while keepingthe user fully informed of everything occurring at each step of asequence. Programming capabilities should include capability to modifythe electronics package's adjustable parameters, to test devicediagnostics, and to store and retrieve telemetered data. It is desirablethat when the implanted unit is interrogated, the present state of theadjustable parameters is displayed on the PC monitor so that theprogrammer may then conveniently change any or all of those parametersat the same time; and, if a particular parameter is selected for change,all permissible values for that parameter are displayed so that theprogrammer may select an appropriate desired value for entry into thepulse generator.

Other desirable features of appropriate software and related electronicswould include the capability to store and retrieve historical data,including patient code, device serial number, number of hours of batteryoperation, number of hours of output, and number of magnetic activations(indicating patient intercession) for display on a screen withinformation showing date and time of the last one or more activations.

Diagnostics testing should be implemented to verify proper operation ofthe device, and to indicate the existence of problems such as withcommunication, the battery, or the lead/electrode impedance. A lowbattery reading, for example, would be indicative of imminent end oflife of the battery and need for implantation of a new device. However,battery life should considerably exceed that of other implantablemedical devices, such as cardiac pacemakers, because of the relativelyless frequent need for activation of the pulse generator of the presentinvention. In any event, the nerve electrodes are capable of indefiniteuse absent indication of a problem with them observed on the diagnosticstesting.

The device may utilize circadian or other programming as well, so thatactivation occurs automatically at normal mealtimes for this patient.This may be in addition to the provision for the manual, periodicbetween meal, and sensing-triggered activation as described aboveherein.

The pulse generator may also be activated manually by the patient by anyof various means by appropriate implementation of the device. Thesetechniques include the patient's use of an external magnet, or of anexternal RF signal generator, or tapping on the surface overlying thepulse generator, to activate the pulse generator and thereby cause theapplication of the desired modulating signal to the electrodes. Anotherform of treatment of may be implemented by programming the pulsegenerator to periodically deliver the vagal activity modulationproductive of glycemic control at programmed intervals.

In some embodiments, the system may include one or more sensors that mayprovide for signals to initiate therapy signals to one or moreelectrodes. For example, a sensor may measure the amount of glucose inthe blood and initiate an upregulating signal to a nerve or organ inorder to modify GLP1 production if the amount of glucose exceeds acertain threshold. In another embodiment, the sensor may measure strainor the presence of food entering the duodenum and apply an upregulatingsignal to the duodenum, small bowel, ileum, splanchnic nerve, or celiacbranch of the vagus nerve.

C. Methods

The disclosure provides methods of treating a subject for a conditionassociated with impaired glucose regulation. In some embodiments, amethod comprises: applying an intermittent electrical signal to a targetnerve at a site with said electrical signal selected to down-regulateand/or up-regulate neural activity on the nerve and with normal orbaseline neural activity restoring upon discontinuance of said block orup-regulation. In embodiments, the method provides for an increase insecretion of GIP and/or GLP-1. In some embodiments, the methods furthercomprise administering a composition to the subject comprising aneffective amount of an agent that increases glycemic control. In someembodiments, the electrical signal is applied to the nerve by implantinga device or system as described herein.

In some embodiments, a method of treating a condition associated withimpaired glucose regulation in a subject comprises applying anintermittent neural conduction block to a target nerve of the subjecthaving impaired glucose regulation at a blocking site with said neuralconduction block selected to down-regulate neural activity on the nerveand to restore neural activity on the nerve upon discontinuance of saidblock.

In other embodiments, methods include a diabetes or prediabetestreatment comprising selecting a drug for treating diabetes or impairedglucose control for a patient where effective dosages for treatingdiabetes or prediabetes for such a patient are associated withdisagreeable side effects or impaired glycemic control; and treating apatient for diabetes or impaired glucose control with a concurrenttreatment comprising: a) applying an intermittent neural block to atarget nerve of the patient at multiple times per day and over multipledays with the block selected to down-regulate afferent and/or efferentneural activity on the nerve and with neural activity restoring upondiscontinuance of said block; and b) administering said drug to thepatient.

In other embodiments, a method of achieving glucose regulation in apatient comprises positioning an electrode on or near the vagus nerve,and an anodic electrode in contact with adjacent tissue; implanting aneurostimulator coupled to the electrodes into the patient, applyingelectrical pulses with defined characteristics of amplitude, pulsewidth, frequency and duty cycle to the vagus nerve wherein the definedcharacteristics are selected to improve glucose regulation in thepatient.

In embodiments, the methods include a method of increasing or modifyingthe amount of GLP1, GIP, or both comprising: applying an intermittentelectrical signal to a target nerve, with said electrical signalselected to up regulate or down-regulate neural activity on the nerveand to restore neural activity on the nerve upon discontinuance of saidsignal, wherein the electrical signal is selected to modify the amountof GLP1, GIP, or both. In some embodiments, the electrical signal isselected for frequency, pulse width, amplitude and timing todownregulate neural activity as described herein. In some embodiments,the electrical signal is selected for frequency, pulse width, amplitudeand timing to upregulate neural activity as described herein. In someembodiments, the electrical signal is selected to modify GLP1. In someembodiments, the electrical signal is selected to increase GLP1,especially when blood glucose is elevated.

In embodiments, the electrical signal is applied intermittently in acycle including an on time of application of the signal followed by anoff time during which the signal is not applied to the nerve, whereinthe on and off times are applied multiple times per day over multipledays. In some embodiments, the on time is selected to have a duration ofabout 30 seconds to about 5 minutes. When the signal is selected todownregulate activity on the nerve, the electrical signal is applied ata frequency of about 200 Hz to 5000 Hz. When the signal is selected toupregulate activity on the nerve, the electrical signal is applied at afrequency of about 1 Hz to 200 Hz.

In embodiments, the electrical signal is applied to an electrodepositioned on the vagus nerve. In some cases, the electrical signal isapplied on the hepatic branch of the vagus nerve. In other cases, theelectrical signal is applied on the celiac branch of the vagus nerve. Insome embodiments, the e electrical signal is applied to an organinvolved in glucose regulation such as the liver, duodenum, jejunum, orileum.

In embodiments, downregulating and upregulating signals are bothapplied. In some cases, the signals are applied at the same time,different times, or overlapping times. In some embodiments, adownregulating signal is applied to a vagus nerve near the esophagus,and an upregulating signal applied to splanchnic nerve or the celiacbranch of the vagus nerve. In some embodiments, a down regulating signalis applied to the vagus nerve near the esophagus and an upregulatingsignal is applied to the duodenum or ileum.

In embodiments, the method further comprises detecting the level of GLP1or GIP to determine whether to apply an electrical signal treatment. Ifthe levels of GLP1 and/or GIP are increased to normal or baseline levelsexpected in a control sample from a subject without diabetes, treatmentto increase GLP1 and/of GIP may cease until the levels fall below theexpected levels required to maintain adequate glucose control. Suchlevels are known or can be determined using methods known to those ofskill in the art.

In embodiments, the method further comprises administering an agent thatimproves glucose control. Such agents include agents that increase theamount of insulin and/or increase the sensitivity of cells to insulin.Nonlimiting examples of agents include insulin, insulin analogs,sulfonylureas, meglitinides, GLP-1 analogs, DPP4 inhibitors, and PPARalpha, gamma, or delta agonists.

Conditions Associated with Impaired Glucose Regulation

Conditions associated with impaired glucose regulation include Type 2diabetes, impaired glucose tolerance, impaired fasting glucose,gestational diabetes, and Type 1 diabetes. “Impaired glucose regulation”refers to alterations in one or more of glucose absorption, glucoseproduction, insulin secretion, insulin sensitivity, GLP-1 regulation,and glucagon regulation.

Type 2 diabetes is a disease in which liver, muscle and fat cells do notuse insulin properly to import glucose into the cells and provide energyto the cells. As the cells begin to starve for energy, signals are sentto the pancreas to increase insulin production. In some cases, thepancreas eventually produces less insulin exacerbating the symptoms ofhigh blood sugar. Patients with Type 2 diabetes have a fasting plasmaglucose of 126 mg/dl or greater; oral glucose tolerance of 200 mg/dl orgreater; and/or % of HbA1C of 6.5% or greater. In some cases, the HbA1Cpercentage is 6-7%, 7-8%, 8-9%, 9-10%, and greater than 10%.

Despite the presence of treatments for type 2 diabetes, not all patientsachieve glucose control or maintain glucose control. A patient that hasnot achieved glycemic control will typically have an HbA1C of greaterthan 7%. In some embodiments, patients are selected that continue tohave problems with glycemic control even with drug treatment.

Patients with impaired glucose tolerance and/or impaired fasting glucoseare those patients that have evidence of some minimal level of lack ofglucose control. Patients can be naïve to any treatment or are thosethat have been treated with one or more pharmaceutical treatments.“Pre-Diabetes” is a term that is used by the American DiabetesAssociation to refer to people who have a higher than normal bloodglucose but not high enough to meet the criteria for diabetes. The lackof glycemic control can be determined by the fasting plasma glucose test(FPG) and/or the oral glucose tolerance test (OGTT). The blood glucoselevels measured after these tests determine whether the patient hasnormal glucose metabolism, impaired glucose tolerance, impaired fastingglucose, or diabetes. If the patient's blood glucose level is abnormalwithin a specified range following the FPG, it is referred to asimpaired fasting glucose (IFG); if the patient's glucose level isabnormal within a specified range following the OGTT, it is referred toas impaired glucose tolerance (IGT). A patient is identified as havingimpaired fasting glucose with a FPG of greater than equal to 100 to lessthan 126 mg/dl and/or impaired glucose tolerance with an OGTT of greaterthan or equal to 140 to less that 200 mg/dl. A person with Pre-Diabetescan have IFG and/or IGT in those ranges.

In some embodiments, patients are selected that are overweight but notobese (have a BMI less than 30) and have Type 2 diabetes, that areoverweight but not obese and have prediabetes, or that have type 2diabetes and are not overweight or obese. In some embodiments, patientsare selected that have one or more risk factors for Type 2 diabetes.These risk factors include age over 30, family history, overweight,cardiovascular disease, hypertension, elevated triglycerides, history ofgestational diabetes, IFG, and/or IGT.

In some embodiments, patients having impaired glucose regulation andthat have gastroparesis may be excluded from the methods as describedherein.

Signal Application

In one aspect of the disclosure a reversible intermittent modulatingsignal is applied to a target nerve or organ in order to downregulateand/or upregulate neural activity on the nerve.

In embodiments of the methods described herein a neural conduction blockis applied to a target nerve at a site with said neural conduction blockselected to down-regulate neural activity on the nerve and with neuralactivity restoring upon discontinuance of said signal. Systems forapplying such a signal are been described U.S. Pat. No. 7,167,750;US2005/0038484 which is incorporated by reference.

In some cases, the nerve is a nerve that innervates one or morealimentary organs, including but not limited to the vagus nerve, celiacnerves, hepatic branch of the vagus nerve, and splanchnic nerve. Thesignal applied may upregulate and/or down regulate neural activity onone or more of the nerves.

In some embodiments, said modulating signal comprises applying anelectrical signal. The signal is selected to down regulate or upregulate neural activity and allow for restoration of the neuralactivity upon discontinuance of the signal. A pulse generator, asdescribed above, can be employed to regulate the application of thesignal in order to alter the characteristic of the signal to provide areversible intermittent signal. The characteristics of the signalinclude location of the signal, frequency of the signal, amplitude ofthe signal, pulse width of the signal, and the administration cycle ofthe signal. In some embodiments, the signal characteristics are selectedto provide for improved glucose regulation.

In some embodiments, electrodes applied to a target nerve are energizedwith an intermittent blocking or down regulating signal. The signal isapplied for a limited time (e.g., 5 minutes). The speed of neuralactivity recovery varies from subject to subject. However, 20 minutes isa reasonable example of the time needed to recover to baseline. Afterrecovery, application of a blocking signal again down-regulates neuralactivity which can then recover after cessation of the signal. Renewedapplication of the signal can be applied before full recovery. Forexample, after a limited time period (e.g., 10 minutes) blocking can berenewed resulting in average neural activity not exceeding a levelsignificantly reduced when compared to baseline. In some embodiments,the electrical signal is applied intermittently in a cycle including anon time of application of the signal followed by an off time duringwhich the signal is not applied to the nerve, wherein the on and offtimes are applied multiple times per day over multiple days. Inembodiments, the on and/or off times are selected to allow at leastpartial recovery of the nerve. While not meant to limit the disclosure,it is believed that allowing a recovery period for the nerve may avoidenteric accommodation.

Recognition of recovery of neural activity, such as vagal activity,permits a treatment therapy and apparatus with enhanced control andenhanced treatment options. FIG. 6 illustrates vagal activity over timein response to application of a blocking signal as described above andfurther illustrates recovery of vagal activity following cessation ofthe blocking signal. It will be appreciated that the graph of FIG. 6 isillustrative only. It is expected there will be significantpatient-to-patient variability. For example, some patients' responses toa blocking signal may not be as dramatic as illustrated. Others mayexperience recovery slopes steeper or shallower than illustrated. Also,vagal activity in some subjects may remain flat at a reduced levelbefore increasing toward baseline activity. However, based on theafore-mentioned animal experiments, FIG. 6 is believed to be a fairpresentation of a physiologic response to blocking.

In FIG. 6, vagal activity is illustrated as a percent of baseline (i.e.,vagal activity without the treatment of the present invention). Vagalactivity can be measured in any number of ways. For example, quantitiesof pancreatic exocrine secretion produced per unit time are an indirectmeasurement of such activity. Also, activity can be measured directly bymonitoring electrodes on or near the vagus. Such activity can also beascertained qualitatively (e.g., by a patient's sensation of bloatedfeelings or normalcy of gastrointestinal motility).

In FIG. 6, the vertical axis is a hypothetical patient's vagal activityas a percent of the patient's baseline activity (which varies frompatient to patient). The horizontal axis represents the passage of timeand presents illustrative intervals when the patient is either receivinga blocking signal as described or the blocking signal is turned off(labeled “No Blocking”). As shown in FIG. 6, during a short period ofreceiving the blocking signal, the vagal activity drops dramatically (inthe example shown, to about 10% of baseline activity). After cessationof the blocking signal, the vagal activity begins to rise towardbaseline (the slope of the rise will vary from patient to patient). Thevagal activity can be permitted to return to baseline or, as illustratedin FIG. 6, the blocking signal can be re-instituted when the vagalactivity is still reduced. In FIG. 6, the blocking signal begins whenthe vagal activity increases to about 50% of baseline. As a consequence,the average vagal activity is reduced to about 30% of the baselineactivity. It will be appreciated that by varying the blocking timeduration and the “no blocking” time duration, the average vagal activitycan be greatly varied.

The signal may be intermittent or continuous. The preferred nerveconduction block is an electronic block created by a signal at the vagusby an electrode controlled by the implantable pulse generator (such aspulse generator 104 or an external controller). The nerve conductionblock can be any reversible block. For example, ultrasound, cryogenics(either chemically or electronically induced) or drug blocks can beused. An electronic cryogenic block may be a Peltier solid-state devicewhich cools in response to a current and may be electrically controlledto regulate cooling. Drug blocks may include a pump-controlledsubcutaneous drug delivery.

With such an electrode conduction block, the block parameters (signaltype and timing) can be altered by pulse regulator and can becoordinated with the upregulating signals. For example, the nerveconduction block is preferably within the parameters disclosed inSolomonow, et al., “Control of Muscle Contractile Force through IndirectHigh-Frequency Stimulation”, Am. J. of Physical Medicine, Vol. 62, No.2, pp. 71-82 (1983). In some embodiments, the nerve conduction block isapplied with electrical signal selected to block the entirecross-section of the nerve (e.g., both afferent, efferent, myelinatedand nomnyelinated fibers) at the site of applying the blocking signal(as opposed to selected sub-groups of nerve fibers or just efferent andnot afferent or visa versa) and, more preferably, has a frequencyselected to exceed the 200 Hz threshold frequency described in Solomonowet al. Further, more preferred parameters are a frequency of 500 Hz(with other parameters, as non-limiting examples, being amplitude of 4mA, pulse width of 0.5 msec, and duty cycle of 5 minutes on and 10minutes off). As will be more fully described, the present inventiongives a physician great latitude in selecting stimulating and blockingparameters for individual patients.

In embodiments of the methods described herein a signal is applied to atarget nerve at a site with said signal selected to up-regulate neuralactivity on the nerve and with neural activity restoring upondiscontinuance of said signal. In some embodiments, an upregulatingsignal may be applied in combination with a down regulating signal inorder to improve glucose regulation. For example, the upregulatingsignal may be applied to splanchnic nerve and/or celiac nerve.

The signal is selected to upregulate neural activity and allow forrestoration of the neural activity upon discontinuance of the signal. Apulse generator, as described above, is employed to regulate theapplication of the signal in order to alter the characteristic of thesignal to provide a reversible intermittent signal. The characteristicsof the signal include frequency of the signal, location of the signal,and the administration cycle of the signal.

In some embodiments, electrodes applied to a target nerve are energizedwith an up regulating signal. The signal is applied for a limited time(e.g., 5 minutes). The speed of neural activity recovery varies fromsubject to subject. However, 20 minutes is a reasonable example of thetime needed to recover to baseline. After recovery, application of an upsignal again up-regulates neural activity which can then recover aftercessation of the signal. Renewed application of the signal can beapplied before full recovery. For example, after a limited time period(e.g., 10 minutes) upregulating signal can be renewed.

In some embodiments, an upregulating signal may be applied incombination with a down regulating signal in order to improve glucoseregulation, decrease the amount of calories ingested or the amount ofglucose absorbed from food, increase/modify the amount and/or secretionof GIP and/or GLP1, and/or decrease the amount of ghrelin secreted. Theneural regulation signals can influence the amount of glucose producedby the liver, the amount of glucose absorbed from food, and the amountof GIP, GLP-1 and/or ghrelin secreted. The neural regulation providesfor a decrease in the amount of insulin required by the subject.

The up-regulating and down-regulating signals may be applied todifferent nerves at the same time, applied to the same nerve atdifferent times, or applied to different nerves at different times. Inembodiments, an up-regulating signal may be applied to a celiac nerve orsplanchnic nerve. In other embodiments, an up-regulating ordownregulating signal may be applied to a hepatic branch of the vagusnerve or the signal may be applied to decrease the amount of hepaticglucose produced, especially in the early morning.

In some embodiments, a downregulating signal is applied to a vagus nervebranch intermittently multiple times in a day and over multiple days incombination with an upregulating signal applied intermittently multipletimes in a day and over multiple days to a different nerve or organ. Insome embodiments, the upregulating signal is applied due to a sensedevent such as the amount of blood glucose present or the entry of foodinto the duodenum. In other embodiments, an upregulating signal appliedto the splanchnic nerve, the celiac nerve, the duodenum and/or the ileumcan be applied during a time period after normal meal times for thesubject typically 15 to 30 minutes after mealtimes or times when glucoselevels rise.

In some cases, signals are applied at specific times. For example, adownregulating signal may be applied before and during meal, followed bya stimulatory signal about 30 to 90 minutes after eating. In anotherexample, a downregulating signal may be applied to the vagus nerve orthe hepatic branch of the vagus nerve early in the morning when hepaticglucose is increasing.

In some embodiments, the signal parameters are adjusted to obtain animprovement in glucose regulation. An improvement, in glucose regulationcan be determined by measurement of fasting glucose, oral glucosetolerance test, and/or the HbA1C or a decrease in the amount of insulinneeded by the subject. In an embodiment, it is preferred that areduction of the HbA1C in absolute percentage is at least 0.4% and morepreferably is any % in the range of 0.4% to 5%. In some embodiments, areduction of the HbA1C in absolute percentage is any one of 0.5%, 1%,1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% or more. For example, a Type 2diabetes patient may have a HbA1C of 9% and a reduction to HbA1C of 6.5%would be a reduction of 2.5% and would represent an improvement inglucose regulation.

In some embodiments, an improvement in glucose regulation comprises afasting glucose of less than 126 mg/dl or greater and/or oral glucosetolerance of less than 200 mg/dl. In some embodiments the fastingglucose and/or oral glucose tolerance is reduced by at least 5% and morepreferably any percentage in the range of 5 to 50%.

In an embodiment, an improvement in glucose regulation comprises one ormore of the following characteristics: a HbA1C of less than or equal to6.5%; less than 100 mg/dl fasting glucose; and/or less than 140 mg/dloral glucose tolerance.

Location of Signal Application

Modulation of neural activity can be achieved by upregulating and/ordown regulating neural activity of one or more target nerves or organs.

In some embodiments, electrodes can be positioned at a number ofdifferent sites and locations on or near a target nerve. Target nervesinclude the celiac nerve, the hepatic nerve, the vagal nerve, thesplanchnic nerve, or some combination of these, respectively, of apatient. The electrode may also be positioned to apply a signal to anorgan in proximity to the vagus nerve such as the liver, duodenum,jejunum, ileum, spleen, pancreas, esophagus, or stomach. In someembodiments, the electrode is positioned to apply an electrical signalto the nerve at a location near or distal to the diaphragm of thesubject.

Electrodes may be positioned on different nerves to apply adown-regulating signal as opposed to an upregulating signal. Forexample, a down regulating signal can be applied on the vagus nerve andan upregulating signal applied to the splanchnic nerve. In someembodiments, the signals may be applied to reduce the neurally mediatedreflex secretion by blocking the vagal nerves to the pancreas, andconcurrently or subsequently, stimulate the splanchnic nerves to inhibitinsulin secretion and/or upregulate the celiac nerve to stimulate GLP1production.

In some embodiments, the electrode is positioned to apply a signal to abranch or trunk of the vagus nerve. In other embodiments, the electrodeis positioned to apply a signal to an anterior trunk, posterior trunk orboth. In some embodiments, the electrodes may be positioned at twodifferent locations at or near the same nerve or on the nerve and on analimentary tract organ. In some embodiments, the electrode is positionedbelow vagal enervation of the heart such as at a subdiaphragmaticlocation.

For example, FIG. 2 illustrates placement of a blocking electrode.Referring to FIG. 2, the baseline vagal activity is illustrated by thesolid line of the proximal vagus nerve segment VNP. The remainder of thevagus and enteric nervous system are shown in reduced thickness toillustrate down-regulation of tone. The pancreo-biliary output (andresulting feedback) is also reduced. In FIG. 2, the blocking electrodeBE is shown high on the vagus relative to the GI tract innervation(e.g., just below the diaphragm), the sole blocking electrode could beplaced lower (e.g., just proximal to pancreo/biliary innervation VN5).Blocking of the entire vagus as described above can be used todown-regulate the vagus for various benefits including treating acondition associated with impaired glycemic control. In someembodiments, the electrode may be placed on the celiac branch of thevagal nerve and provide for an upregulating signal.

In other embodiments, alternative designs for placing electrodes on ornear the vagus nerve in a region of the esophagus E either above orbelow the diaphragm are provided.

Two paired electrodes may connect to a pulse generator for bi-polarsignal. In other embodiments, a portion of the vagus nerve VN isdissected away from the esophagus E. An electrode is placed between thenerve VN and the esophagus E. The electrode is placed overlying thevagus nerve VN on a side of the nerve opposite electrode and withelectrodes axially aligned (i.e., directly across from one another). Notshown for ease of illustration, the electrodes may be carried on acommon carrier (e.g., a PTFE or silicone cuff) surrounding the nerve VN.Other possible placements of electrodes are described herein US2005/0131485 published Jun. 16, 2005, which patent publication is herebyincorporated by reference.

Signal Frequency and Timing

In some embodiments, a downregulating signal has a frequency of at least200 Hz and up to 5000 Hz. In other embodiments, the signal is applied ata frequency of about 500 to 5000 Hz. Applicant has determined a mostpreferred blocking signal has a frequency of 3,000 Hz to 5,000 Hz orgreater applied by two or more bi-polar electrodes. Such a signal has apreferred pulse width of 100 micro-seconds (associated with a frequencyof 5,000 Hz). It is believed this frequency and pulse width best avoidneural recovery from blocking and avoid repolarization of the nerve byavoiding periods of no signal in the pulse cycle. A short “off” time inthe pulse cycle (e.g., between cycles or within a cycle) could beacceptable as long as it is short enough to avoid nerve repolarization.The waveform may be a square or sinusoidal waveform or other shape. Thehigher frequencies of 5,000 Hz or more have been found, in porcinestudies, to result in more consistent neural conduction block.Preferably the signal is bi-polar, bi-phasic delivered to two or moreelectrodes on a nerve.

In some embodiments, a signal amplitude of 0.5 to 8 mA is adequate forblocking. Other amplitudes may suffice. Other signal attributes can bevaried to reduce the likelihood of accommodation by the nerve or anorgan. These include altering the power, waveform or pulse width.

Upregulating signals typically comprise signals of a frequency of lessthan 200 Hz, more preferably 10 to 150 Hz, and more preferably 10 to 50Hz.

Selection of a signal that upregulates and/or downregulates neuralactivity and/or allows for recovery of neural activity can involveselecting signal type and timing of the application of the signal. Forexample, with an electrode conduction block, the block parameters(signal type and timing) can be altered by the pulse generator and canbe coordinated with the stimulating signals. The precise signal toachieve blocking may vary from patient to patient and nerve site. Theprecise parameters can be individually tuned to achieve neuraltransmission blocking at the blocking site.

In some embodiments, the signal has a duty cycle including an ON timeduring which the signal is applied to the nerve followed by an OFF timeduring which the signal is not applied to the nerve. For example, the ontime and off times may be adjusted to allow for partial recovery of thenerve, especially in situations where enteric accommodation may occur.In some cases, the downregulating and upregulating signals can becoordinated so that the upregulating signals are applied when downregulating signals are not being applied such as when the upregulatingsignals are applied at specific times or due to sensed events. In someembodiments, a sensed event indicates that an upregulating signal isapplied and a down regulating signal is not applied for a time periodrelating to the sensed event, e.g. glucose exceeding a certain thresholdor food entering the duodenum.

In some embodiments, subjects receive an implantable component 104.(FIG. 3) The electrodes 212, 212 a are placed on the anterior vagusnerve AVN and posterior vagus nerve PVN just below the patient'sdiaphragm. The external antenna (coil 102) is placed on the patient'sskin overlying the implanted receiving coil 105. The external controlunit 101 can be programmed for various signal parameters includingoptions for frequency selection, pulse amplitude and duty cycle. Forblocking signals, the frequency options include 2500 Hz and 5000 Hz(both well above a threshold blocking frequency of 200 Hz). The vastmajority of treatments are at 5,000 Hz, alternating current signal, witha pulse width of 100 microseconds. The amplitude options are 1-8 mA. Forstimulating signals, a frequency is selected of less than 200 Hz.

Duty cycle could also be controlled. A representative duty cycle is 5minutes of on time followed by 5 minutes of no signal. The duty cycle isrepeated throughout use of the device.

FIG. 12 shows an exemplary duty cycle. Each ON time includes a ramp-upwhere the 5,000 Hz signal is ramped up from zero amperes to a target of6-8 mA. Each ON time further includes a ramp-down from full current tozero current at the end of the ON time. For about 50% of the patients,the ramp durations were 20 seconds and for the remainder the rampdurations were 5 seconds. In some embodiments, the on time is elected tohave a duration of no less than 30 seconds or no more than 180 secondsor both.

The use of ramp-ups and ramp-downs are conservative measures to avoidpossibility of patient sensation to abrupt application or termination ofa full-current 5,000 Hz signal. An example of a ramp-up for a highfrequency signal is shown in U.S. Pat. No. 6,928,320 to King issued Aug.9, 2005.

In some embodiments, a mini duty cycle can be applied. In an embodiment,a mini duty cycle comprises 180 millisecond periods of mini-ON times of5,000 Hz at a current which progressively increases from mini-ON time tomini-ON time until full current is achieved (or progressively decreasesin the case of a ramp-down). Between each of such mini-ON times, thereis a mini-OFF time which can vary but which is commonly about 20milliseconds in duration during which no signal is applied. Therefore,in each 20-second ramp-up or ramp-down, there are approximately onehundred mini-duty cycles, having a duration of 200 milliseconds each andeach comprising approximately 180 milliseconds of ON time andapproximately 20 milliseconds of OFF time.

In some embodiments, an upregulating signal may be applied incombination with a down regulating signal in order to improve glucoseregulation, decrease the amount of calories ingested as well as increasethe amount of GIP and/or GLP1. For example, a downregulating signal maybe applied before and during meal, followed by an upregulating signalabout 30 to 90 minutes after eating.

Normally a patient would only use the device while awake. The hours oftherapy delivery can be programmed into the device by the clinician(e.g., automatically turns on at 7:00 AM and automatically turns off at9:00 PM). In some cases, the hours of therapy would be modified tocorrespond to times when blood sugar fluctuates such as before a mealand 30-90 minutes after eating. For example, the hours of therapy may beadjusted to start at 5:00 AM before breakfast and end at 9:00 PM orlater depending on when the last meal or snack is consumed. In theRF-powered version of the pulse generator, use of the device is subjectto patient control. For example, a patient may elect to not wear theexternal antenna. The device keeps track of usage by noting times whenthe receiving antenna is coupled to the external antenna throughradio-frequency (RF) coupling through the patient's skin.

In some cases, loss of signal contact between the external controller101 and implanted pulse generator 104 occurs in large part tomisalignment between coils 102, 105. (See FIG. 8). It is believed coilmisalignment results from, at least in part, changes in body surfacegeometry throughout the day (e.g., changes due to sitting, standing orlying down). These changes can alter the distance between coils 102,105, the lateral alignment of the coils 102, 105 and the parallelalignment of the coils 102, 105. Misalignment can be detected by thedevice and alignment of the coils adjusted to ensure that the signalsare restored. The device may include a notification to the patient orphysician if there has been a misalignment.

In some embodiments, the external component 101 can interrogate thepulse generator component 104 for a variety of information. In someembodiments, therapy times of 30 seconds to 180 seconds per duty cycleare preferred to therapy times of less than 30 seconds per duty cycle orgreater than 180 seconds per duty cycle.

During a 10 minute duty cycle (i.e., intended 5 minutes of therapyfollowed by a 5 minute OFF time), a patient can have multiple treatmentinitiations. For example, if, within any given 5-minute intended ONtime, a patient experienced a 35-second ON time and 1.5 minute actual ONtime (with the remainder of the 5-minute intended ON time being a periodof no therapy due to signal interruption), the patient could have twoactual treatment initiations even though only one was intended. Thenumber of treatment initiations varies inversely with length of ON timesexperienced by a patient.

The flexibility to vary average neural activity, such as vagal activity,gives an attending physician great latitude in treating a patient. Forexample, in treating diabetes or prediabetes, the blocking signal can beapplied with a short “no blocking” time. If the patient experiencesdiscomfort due to dysmotility, the duration of the “no blocking” periodcan be increased to improve patient comfort. Also, the reduction ofenzyme production can result in decreased fat absorption withconsequential increase of fat in feces. The blocking and no blockingduration can be adjusted to achieve tolerable stool (e.g., avoidingexcessive fatty diarrhea). The control afforded by the present inventioncan be used to prevent the enteric nervous system's assumption ofcontrol since vagal activity is not completely interrupted as in thecase of a surgical and permanent vagotomy.

While patient comfort may be adequate as feedback for determining theproper parameters for duration of blocking and no blocking, moreobjective tests can be developed. For example, the duration of blockingand no blocking as well as combination with upregulating signals can beadjusted to achieve desired levels of glucose regulation. Such testingcan be measured and applied on a per patient basis or performed on astatistical sampling of patients and applied to the general populationof patients.

In some embodiments, a sensor may be employed. A sensing electrode SEcan be added to monitor neural activity as a way to determine how tomodulate the neural activity and the duty cycle. While sensing electrodecan be an additional electrode to blocking electrode, it will beappreciated a single electrode could perform both functions. The sensingand blocking electrodes can be connected to a controller as shown inFIG. 3. Such a controller is the same as controller 102 previouslydescribed with the additive function of receiving a signal from sensingelectrode.

In some embodiments, the sensor can be a sensing electrode, a glucosesensor, or sensor that senses other biological molecules or hormones ofinterest. When the sensing electrode SE yields a signal representing atargeted maximum vagal activity or tone (e.g., 50% of baseline as shownin FIG. 6) the controller with the additive function of receiving asignal from sensing electrode energizes the blocking electrode BE with ablocking signal. As described with reference to controller 102,controller with the additive function of receiving a signal from sensingelectrode can be remotely programmed as to parameters of blockingduration and no blocking duration as well as targets for initiating ablocking signal or upregulating signal.

In some embodiments, of the apparatus and method described herein userecovery of the vagus nerve to control a degree of down-regulation ofvagal activity. This gives a physician enhanced abilities to control apatient's therapy for maximum therapeutic effectiveness with minimumpatient discomfort. Vagal neural blocking simulates a vagotomy but,unlike a vagotomy, is reversible and controllable.

Agents that Alter Impairment of Glycemic Control of the Subject

The disclosure provides methods for treating a condition associated withimpaired glucose regulation that include neuroregulation as well asadministering to a subject a composition comprising an agent thataffects glucose control in a subject. In some embodiments, the agentincreases the amount of insulin present in the blood. In otherembodiments, the agent increases insulin sensitivity. In someembodiments, the agent reduces endogenous glucose production and/orglucose absorption.

Several pathways are known to affect energy balance. Pathways includegut-hypothalamic axis (e.g. ghrelin), gut-hindbrain axis (e.g. vagusnerve), peripheral tissue (adipose tissue, skeletal muscle)-hypothalamicaxis (e.g. leptin), and hypothalamic-hindbrain axis (neuralprojections). In particular, the hypothalamus (forebrain) and the areapostrema (hindbrain) are 2 regions of the central nervous system whichare thought to play orchestrating roles in the human energy homeostasis.It has been documented that there are neural connections between thesetwo regions enabling communications and complementary, as well as,redundant effects on body energy balance. Numerous hormones, enzymes,neurotransmitters, and other mediators are released from different partsof these pathways and can have influences on these regions of thecentral nervous system. Utilization of distinct treatment modalitiesthat involve different parts of these pathways and brain regions, thusaltering the communication between the central nervous system and gut,pancreas, liver, muscle, and fat cells may be of importance incombinatorial therapy that is highly effective, robust, and durable.

Agents that affect impaired glucose control can be selected based on anability to complement treatment of applying a signal to alter neuralactivity of a target nerve. As described herein, an agent is selectedthat may provide a complementary or synergistic effect with theapplication of signal to modulate neural activity on a target nerve suchas the vagus nerve. A synergistic or complementary effect can bedetermined by determining whether the patient has an improvement inglycemic control as described herein as compared to one or bothtreatments alone.

In some embodiments, agents that act at a different site (e.g.hypothalamus or pituitary) or through a different pathway may beselected for use in the methods described herein. Agents that complementtreatment are those that include a different mechanism of action foraffecting the glycemic control of the subject. In some embodiments, asynergistic effect may be observed with an agent that does not affectglucose digestion and/or delay gastric emptying, such as an agent thatincreases insulin secretion, insulin sensitivity, and/or decreasesendogenous glucose production. Such agents include insulin, amylinanalogues, insulin secretagogues, sulfonylureas, meglitinides and PPARalpha, gamma and delta agonists.

An agent may also or in addition be selected to be administered that mayhave undesirable side effects at the recommended dosage that preventsuse of the agent, or that provides inadequate glycemic control. Inaddition, patients that have hypertension, cardiac conditions, liverdisease, or renal disease may not be able to tolerate treatment with oneor more of the agents at the recommended dosage due to adverse sideeffects.

Agents that have undesirable side effects include Avandia(rosiglitazone; PPAR-gamma agonist) which has been shown to have adverseeffects on cardiovascular conditions and cause weight gain. Drugs thatinhibit or slow gastric emptying, such as amylin analogs or GLP-1analogs, or drugs that are irritants to the GI track, such as metformin(biguinide) can cause nausea, vomiting, and diarrhea. Drugs that alterbreakdown and absorption of carbohydrate in the GI track, such asPrecose (acarbose; alpha-glucosidase inhibitor) can cause diarrhea andflatulence. Drugs that increase blood insulin concentrations, such asexogenous insulin administration, sulfonylureas, and meglitinides cancause hypoglycemia and weight gain.

Combining administration of a drug with undesirable side effects withmodulating neural activity on a target nerve may allow foradministration of the drugs at a lower dose thereby minimizing the sideeffects. In addition, a drug may be selected that has alteredpharmacokinetics when absorption is slowed by a delay in gastricemptying due to neural downregulation as described herein. In otherembodiments, the recommended dosage may be lowered to an amount that hasfewer adverse side effects. In embodiments, it is expected that therecommended dosage may be able to be lowered at least 25%. In otherembodiments, the dosage can be lowered to any percentage of at least 25%or greater of the recommended dose. In some embodiments, the dosage islowered at least 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90,95, or 100% of the recommended dosage.

In an embodiment, a method provides a treatment for a conditionassociated with impaired glycemic control. A method comprises selectinga drug useful for treating Type 2 diabetes or impaired glucoseregulation and having a recommended dosage for efficacy where a patientis likely to experience disagreeable side effects at said recommendeddosage; and treating the patient with a concurrent treatment comprising:applying an intermittent neural block to a target nerve of the patientat multiple times per day and over multiple days with the block selectedto down-regulate afferent and/or efferent neural activity on the nerveand with neural activity restoring upon discontinuance of said block;and administering said drug to the patient at a dosage less than saidrecommended dosage. In some embodiments, the effective dosages fortreating a condition associated with impaired glycemic control for sucha patient are associated with disagreeable side effects contributing tosaid patient not complying with a drug treatment. In some embodiments,patients are those that have an eating disorder, hypertension, cardiacconditions, liver, or renal disorder and may not be able to toleratetreatment with one or more of the agents.

Agents that increase the amount of insulin present or the amount ofinsulin secreted are agents that can improve glycemic control of thepatient. Such agents include sulfonylureas, meglitinides, Dipeptidylpeptidase IV (DPP4) inhibitors, insulin, insulin analogs, and GLP-1analogs.

Agents that increase the sensitivity of cells to insulin are agents thatcan improve glycemic control of the patient. Such agents includebiguinides such as metformin and PPAR gamma agonists such asrosiglitazone and piglitazone.

Agents that inhibit the production of glucose or the digestion ofcarbohydrates are agents that can improve glycemic control of thepatient. Such agents include biguanides, alpha glycosidase inhibitor,amylin analogs, DPP4 inhibitors, and GLP-1 analogs.

Agents that decrease the effects of gherlin may also be useful indiabetes therapies including protein kinase A inhibitors, neuropeptide Yreceptor inhibitors, and growth hormone secretatogue receptors.

Agents that enhance the amount of GIP or GLP-1 or that decrease theamount ghrelin can be advantageously combined with neural modulationtherapy. For example, up or downregulation of the nerve can be appliedto increase the amount of GIP and/or GLP-1 in combination with an agentssuch as a DPP4 inhibitor which inhibits the breakdown of GLP-1. In anembodiment, the vagus nerve can be downregulated by applying anintermittent reversible downregulating signal to the vagus nerve incombination with a DDP4 inhibitor such as vildagliptin or sitagliptin.

One or more of these agents may be combined for treatment especiallywhen single drug treatment alone does not provide adequate glycemiccontrol. Any of the FDA approved drugs for treating diabetes may also becombined with the methods as described herein.

Dosages for administration to a subject can readily be determined by oneof skill in the art. Guidance on the dosages can be found, for example,by reference to other drugs in a similar class of drugs. For example,dosages have been established for any of the approved drugs or drugs inclinical trials and the range of dose will depend on the type of drug.For example, pramlintide dosages range from about 240 micrograms up to720 micrograms per day. Dosages associated with adverse side effects areknown or can also be readily determined based on model studies. Adetermination of the effective doses to achieve improved glycemiccontrol while minimizing side effects can be determined by animal orhuman studies.

Agents will be formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the clinicalcondition of the individual patient, the cause of the disorder, the siteof delivery of the agent, the method of administration, the schedulingof administration, and other factors known to medical practitioners. Theagent need not be, but is optionally formulated with one or more agentscurrently used to prevent or treat the disorder in question. Theeffective amount of such other agents depends on the amount of agentthat improves glycemic control of the subject present in theformulation, the type of disorder or treatment, and other factorsdiscussed above. These are generally used in the same dosages and withadministration routes as used hereinbefore or about from 1 to 99% of theheretofore employed dosages.

Therapeutic formulations comprising the agent are prepared for storageby mixing the agent having the desired degree of purity with optionalphysiologically acceptable carriers, excipients or stabilizers(Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)),in the form of aqueous solutions, lyophilized or other driedformulations. Acceptable carriers, excipients, or stabilizers arenontoxic to recipients at the dosages and concentrations employed, andinclude buffers such as phosphate, citrate, histidine and other organicacids; antioxidants including ascorbic acid and methionine;preservatives (such as octadecyldimethylbenzyl ammonium chloride;hexamethonium chloride; benzalkonium chloride, benzethonium chloride;phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol);low molecular weight (less than about 10 residues) polypeptides;proteins, such as serum albumin, gelatin, or immunoglobulins;hydrophilic polymers such as polyvinylpyrrolidone; amino acids such asglycine, glutamine, asparagine, histidine, arginine, or lysine;monosaccharides, disaccharides, and other carbohydrates includingglucose, mannose, or dextrins; chelating agents such as EDTA; sugarssuch as sucrose, mannitol, trehalose or sorbitol; salt-formingcounter-ions such as sodium; metal complexes (e.g., Zn-proteincomplexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ orpolyethylene glycol (PEG).

The formulation herein may also contain more than one active compound asnecessary for the particular indication being treated. In suchembodiments, the compounds have complementary activities that do notadversely affect each other. Such molecules are suitably present incombination in amounts that are effective for the purpose intended.

The therapeutic agent is/are administered by any suitable means,including parenteral, subcutaneous, orally, intradermal,intraperitoneal, and by aerosol. Parenteral infusions includeintramuscular, intravenous, intraarterial, intraperitoneal, orsubcutaneous administration. Pumps may be utilized as well as drugeluting devices and capsules.

Example 1 Material and Methods/Experimental Design

An open-label, prospective, baseline-controlled, three-center clinicalstudy was conducted to evaluate feasibility and safety and efficacy of adevice as described herein that causes intermittent electrical blockingof the anterior and posterior vagal trunks. The participating centersinclude Flinders Medical Centre, Adelaide, Australia; Instituto Nationalde la Nutricion (INNSZ), Mexico City, Mexico; and, St. Olavs UniversityHospital, Trondheim, Norway.

Patients

Male or female obese subjects (BMI 31.5-55 kg/m²) 25-60 years of ageinclusive, were recruited at the three centers. The study assesseddevice safety and efficacy for 6 months.

Ability to complete all study visits and procedures was an eligibilityrequirement. Relevant exclusion criteria included: current type 1diabetes mellitus (DM) or type 2 DM poorly controlled with oralhypoglycemic agents or with associated autonomic neuropathy, includinggastroparesis; treatment with weight-loss drug therapy or smokingcessation within the prior three months or reductions of more than 10%of body weight in the previous 12 months; prior gastric resection orother major abdominal surgery, excluding cholecystectomy andhysterectomy; clinically significant hiatal hernias or intra-operativelydetermined hiatal hernia requiring surgical repair or extensivedissection at esophagogastric junction at time of surgery; and presenceof a permanently implanted electrical powered medical device orimplanted gastrointestinal device or prosthesis.

Concurrent treatment for thyroid disorders, epilepsy or depression withtricyclic agents was acceptable for participation if the treatmentregimen was stable for the prior six months.

Implantation of Device

The device included two electrodes (one for each vagal trunk), aneuroregulator (pulse generator) placed subcutaneously and an externalcontroller to program the device.

Under general anesthesia, two leads (electrodes) of the vagal blockingsystem (FIG. 4) were implanted laparoscopically. Device implantation bythe experienced surgeons participating in the study typically took 60 to90 minutes; five ports were usually used. The electrode itself had anactive surface area of 10 mm² and was “c”-shaped to partially encirclethe nerve.

Intra-abdominal dissection and electrode placement were accomplished inthe following sequence. The gastrohepatic ligament was dissected toexpose the esophagogastric junction (EGJ), and the stomach was retracteddownward and laterally in order to keep slight tension on the EGJ. Tolocate the posterior vagal trunk, the right diaphragmatic crus wasidentified and separated from its esophageal attachments. The anteriorvagal trunk was identified by locating it as it courses through thediaphragmatic hiatus. After both vagal trunks had been identified, aright angle grasper was used to dissect a 5 mm window underneath theposterior vagal trunk. The electrode was then placed by positioning aright angle grasper through the window that had been created under thevagal trunk. The electrode's distal suture tab was then grasped, and theelectrode was pulled into place, seating the nerve within the electrodecup. The same steps were repeated to place a second electrode around theanterior vagal trunk. Finally, each electrode was secured in positionusing a single suture placed through each electrode's distal suture taband affixed to the outer layers of the esophagus.

The leads were then connected to the neuroregulator, and it wasimplanted in a subcutaneous pocket in the mid-line just below thexiphoid process. Proper electrode placement was then determined in twodifferent ways at implant. First, correct anatomic electrode-nervealignment was verified visually. Secondly, effective electrical contactwas verified using impedance measurements intra-operatively and atfrequent intervals thereafter. After recovery from the surgery, aprogrammable external controller which contained a rechargeable powersource was used to communicate transdermally with the implantedneuroregulator via an external transmit coil

Electrical Signal Application

The external controller was programmed for frequency, amplitude and dutycycle. The therapeutic frequency selected to block neural pulses on thevagal trunks was 5000 Hz, based on animal studies of vagal inhibition ofpancreatic exocrine secretion. Amplitudes utilized ranged from 1-6 mA;however, in almost all instances, the amplitude was 6 mA. The device wasactivated in the morning, and turned off before sleep. The protocolspecified an algorithm of five minutes of blocking alternating with fiveminutes without blocking for 12 hours per day. Effective electricalcontact was verified using impedance measurements at frequent intervalspostoperatively.

Experimental Therapy and Follow-Up Studies

In order to focus on the effects of the vagal blocking system, the studysubjects were precluded from receiving either concomitant diet orbehavioral counseling or drug therapy for obesity during the 6 monthtrial period. All study participants were implanted with the device. Twoweeks post-implant, intermittent, high-frequency electrical algorithmswere commenced in all subjects. Subjects were followed weekly for 4weeks, then every two weeks until 12 weeks and then monthly visits forbody weight, physical examination and adverse event (AE) inquiry. Inaddition, 12-lead electrocardiograms (ECGs) and clinical chemistrieswere analyzed at a core laboratory.

Calculation of Percentage Excess Weight Loss

Ideal body weight was calculated by measuring each subject's height andthen determining the body weight that would result in a BMI of 25.0 forthat subject, i.e., ideal body weight (kg)=25×height² (m). EWL wascalculated by dividing weight loss by excess body weight [(total bodyweight)−(ideal body weight)] and multiplying by 100. Thus, EWL %=(weightloss (kg)/excess body weight (kg))×100.

Calorie Intake, Dietary Composition, Satiation, Satiety and VagalFunction Studies

Two sub-studies were performed to assess the effect of the treatment onsatiation, calorie intake and vagal function and their relationship tothe degree of weight loss.

In one sub-study (Sub-study A), which was conducted at a single center(Flinders Medical Centre, Adelaide, Australia), all subjects werefollowed with seven-day diet records to quantify changes in calorieintake, dietary composition, satiation at meals and satiety (reducedhunger) between meals. These assessments were conducted pre-implant andafter four weeks, 12 weeks and 6 months of vagal blocking via a dietdiary completed by each subject. At each visit, each seven-day dietrecord, including quantification of carbohydrates, fat and protein as apercent of total caloric intake, was verified during a detailedinterview with a nutritionist. A validated program (Food Works™) fordetermining nutrient and calorie content in food was used. In addition,at each visit, questionnaires with standard, horizontal (100-mm) visualanalog scales (VAS) were used to assess satiation and satiety using bothone-week and 24-hour recall.

In a second sub-study (Sub-study B) conducted after 12 weeks of vagalblocking at two centers (Flinders Medical Centre, Adelaide Australia andInstituto National de la Nutricion, Mexico City, Mexico), a standardizedsham feeding protocol was used in order to assess vagal down-regulation.The endpoint of down-regulation was measured as the inhibition of plasmapancreatic polypeptide (plasma PP) response following sham feeding.Subjects were instructed to fast for at least eight hours prior to thetest. Two baseline plasma samples were obtained for PP levels at −5 and−1 minutes, followed by a 20-minute sham feeding using the “chew andspit” method with blood samples collected every 5 minutes. Subjects wereinstructed to avoid swallowing food or saliva to eliminate nutrientactivation of pancreatic secretion. Plasma was stored at −70 degreesCelsius, and transferred on dry ice for PP levels to be measured bystandard radio-immunoassay (Mayo Medical Laboratories, Rochester, Minn.,USA). A subset of these subjects (n=10) also had sham feeding and plasmaPP levels prior to implantation as part of the familiarization of thecenters with the performance of the test procedure, prior to conductingthe test as planned 12 weeks post-therapy.

Data and Statistical Analysis

Baseline characteristics and demographics were summarized usingdescriptive statistics. Continuous variables were summarized by meanvalues and corresponding standard errors of the mean (SEM). Categorical(including binary) variables were summarized by frequency distributions.

The primary endpoint for assessing the effect on weight loss was themean percent excess weight loss (EWL %) at specified time points (4 and12 weeks and 6 months) and compared to zero in a two-sided, one-samplet-test at the 5% significance level. P-values reported were unadjustedfor multiple comparisons. However, the statistical significance was notaltered after applying Hochberg's multiple comparison procedure.Additionally, a mixed model, repeated measures regression analysis wasconducted evaluating effects of treatment on EWL % over time.

Changes in heart rate and blood pressure were summarized over time,using mean and SEM. ECG recordings were collected and analyzed by anindependent core lab (Mayo Medical Laboratories, Rochester, Minn., USA).Clinical chemistries (amylase, lipase, and blood glucose) were collectedand analyzed according to mean changes from baseline as well ascategorically to determine the frequency of abnormal findings duringfollow-up.

Adverse events (AE) were tabulated and reported. No formal statisticalanalyses of adverse events were performed on the rate of occurrence ofadverse events as no a priori hypotheses were specified.

The changes from baseline in the percentage composition of each dietarymacronutrient component (carbohydrate, protein and fat) was compared tozero in a two-sided, one-sample t-test at each follow-up visit (4 and 12weeks and 6 months) and also in a mixed model, repeated measuresregression model.

Visual analog scale (VAS) questionnaires were completed by each subjectat every follow-up visit to assess satiation and satiety (reducedhunger). Mean changes (±SEM) in responses from baseline were calculatedat each visit.

Plasma PP levels in response to sham feeding were computed as means(±SEM) at 5, 10, 15 and 20 minutes into the sham feeding in participantswho underwent the studies pre-implant and after 12 weeks of vagalblocking. The proportion of subjects with plasma PP increases less ormore than 25 pg/ml (the cut-off value for abnormal vagal function in theliterature) was calculated and the average weight loss for the twogroups compared using a two-tailed, unpaired t-test.

Results

Participants, Demographics and Outcomes of Surgical Procedure

Thirty-one subjects (mean body mass index 41.2±0.7 kg/m²; range 33-48)received the device. Demographics, including type 2 diabetes mellitussubjects, are shown in Table I.

TABLE I Demographics of study population (mean ± SEM) Demographics Allsubjects Number 31 Age (yrs) 41.4 ± 1.4 Gender 26 female/5 maleRace/ethnicity 12 hispanic/19 white-not hispanic Baseline BMI, kg/m²41.2 ± 0.7 Pts with type 2 diabetes mellitus  3

There have been no major intra-operative complications with implantationof the device. Specifically, we have not encountered organ perforation,significant bleeding, post-operative intra-peritoneal infections, orelectrode migration or tissue erosion. The devices were left in placeafter the 6 month study. Those participants continue to be followed aspart of a safety cohort for such a device, and further studies are beingconducted to determine whether the electrical parameters can be modifiedto maximize the efficacy of the device.

Weight Loss

Mean excess weight loss at 4 and 12 weeks and 6 months following deviceimplant was 7.5%, 11.6% and 14.2%, respectively (all changes weresignificant compared to baseline, p<0.0001). Beneficial overall effectsof treatment were observed at all three centers. FIG. 7 shows thedistribution of EWL percentage changes, including the median,interquartile distribution and 5^(th) and 95^(th) percentile withindividuals' data plotted for those beyond those percentiles. Note thatwhile a few individuals did not lose any weight, three patients had >30%EWL at six months, and a quarter of the patients had >25% EWL.

Adverse Events

There were no deaths, no serious adverse events (SAE) related to eitherthe medical device or VBLOC therapy and no unanticipated adverse deviceeffects during the study. Three subjects, who had SAEs that wereunrelated to the device or with vagal blocking therapy, required briefhospitalization: one post-operative lower respiratory tract infection (1day hospitalization), one subcutaneous implant site seroma (3 dayshospitalization), and one case of Clostridium difficile diarrhea twoweeks into the trial period (5 days hospitalization). These three SAEswere completely reversible, and the patients continued in the study.

There were no clinically significant changes in either clinicalchemistries or ECG findings during the 6 month study as evaluated by anexternal data safety monitoring committee (data not shown). There weresmall decreases in heart rate and systolic and diastolic blood pressures(FIG. 8) that were deemed to be non-clinically significant.

Calorie Intake, Dietary Composition, Satiation and Satiety: Sub-Study A

Changes in calorie intake, dietary composition, satiation and satiety(decreased hunger) were assessed in all ten subjects who completed thevisits and procedures at Flinders Medical Centre, Adelaide, Australia aspart of Sub-study A. Calorie intake decreased by >30% at 4 and 12 weeksand 6 months (p<0.01, all time points, FIG. 9). Relative amount ofcarbohydrate, protein, and fat intake stayed stable. In addition, VASquestionnaire data based on 24-hour recall demonstrated that subjectsreported earlier satiation (fullness) at main meals (FIG. 10A, p.<0.001)and enhanced satiety (decreased hunger) between meals (FIG. 10B,p=0.005) in the 6 month time period.

Vagal Function: Sub-Study B

Twenty-four study patients completed the sham feeding protocol after 12weeks of intermittent vagal blocking as part of Sub-study B. Prior toimplant, sham feeding resulted in normal plasma PP response (increasesabove baseline of ≧25 pg/ml: 42±19 pg/ml). Following 12 weeks of vagalblocking, PP responses at 20 min were suppressed, so that the increasesin plasma PP were on average <25 pg/ml (20±7 pg/ml). The percentages ofsubjects with blunted PP response (<25 pg/ml) were 88, 79, 71 and 67% at5, 10, 15 and 20 min, respectively. Importantly, a subset analysis ofdata at 12 weeks showed that weight loss was significantly greater inthe 14 patients who never had plasma PP rise >25 pg/ml over fasting,compared to the 10 patients who had plasma PP rise >25 pg/ml (p=0.02,FIG. 11).

Change in Glycemic Control

A subset of patients from the above study, as well as other clinicaltrial studies, were monitored for hemoglobin A1c using standard methods.At baseline, the mean of 10 patients was 8.2% HbA1c. After 4 weeks themean HbA1C dropped to 7.1%. Improvements were noted as early as 4 weeksand before substantial weight loss was observed.

TABLE 2 HemoglobinA1c Time point (mean ± SEM) Baseline 8.2 ± 0.6% Week 47.1 ± 0.4% Improvement −1.1 ± 0.3%* N = 10 *p = 0.002

Discussion

In this clinical trial of an implantable system that deliversintermittent vagal blocking (VBLOC therapy), we report here on initialdata on safety and efficacy—as measured by EWL %. In addition, thesub-studies conducted have shown that the weight loss is associated withdecreased calorie intake, earlier satiation at meals and enhancedsatiety (decreased hunger) between meals. A subset of patientsdemonstrated a significant decrease in HbA1c as early as 4 weeks. Vagalinhibition, measured by reduced plasma PP response during sham feeding(<25 pg/ml), was demonstrated at three months post implant, suggestingthat the electrical signal delivered via VBLOC therapy is able tomaintain vagal blockade and to induce the clinical effects on satiationand weight loss.

The magnitude of EWL ranged from 1.2 to 36.8% at six months, suggestingthat there is variability in the response and room for maximizing thebenefit from such a treatment approach. It should be noted that a singlestudy subject, who was non-compliant during the entire course of thestudy, did gain weight. This subject's compliance was deemed inadequateas reflected by the fact that therapy delivery was less than 25% of thatprescribed during the 6 month study period. Variable response to vagalblock may reflect several possibilities including failure to apply theelectrical treatment (compliance), inter-individual differences in the“capture” of vagal function (as illustrated by the suboptimalsuppression of the plasma PP response to sham feeding), and technicalfactors in the device, such as variability in the position of theexternal coil relative to the internal neuroregulator.

Weight reduction observed in this study was progressive out to 6 monthsof follow-up without an apparent plateau. It is important to note thatthis effect on weight was achieved without the additional benefit ofdietary or behavioral modification, which may augment weight reductionwith any intervention. While we cannot completely exclude a placeboeffect, given the open trial design, we expect that this is unlikelysince the reduced caloric intake, time to satiation at meals and hungerbetween meals were achieved early after onset of treatment, weremaintained throughout the 6 month study, and were associated withsignificant and sustained weight loss.

The present studies provide some insights on the mechanism for theweight loss associated with VBLOC therapy. The vagus nerve has pivotalroles in multiple aspects of alimentary tract function, includinggastric accommodation, contractions and emptying and pancreatic exocrinesecretion. It has also been reported that the vagus nerve plays animportant role in release of gut-derived hormones known to have acuteand profound effects on food intake and appetite. A prime example ofsuch a vagally-controlled hormone is ghrelin, an orexigenic peptidelargely produced in the foregut. Ghrelin concentrations increase withshort-term food deprivation and/or weight loss and decrease rapidly withfood intake. Thus, it is believed that ghrelin has an anticipatory rolein food intake. Bilateral vagotomy in rats has been reported tocompletely eliminate the expected increase in ghrelin levels induced byfood deprivation. This elimination of the ghrelin response may be amechanism whereby vagal blocking results in reduced food intake andaugmented satiation.

Safety of the novel device and electrical signal applied as describedherein is supported by the fact that the only notable complications werethree infections related to the surgical procedure or C. difficilediarrhea, all of which were considered by an independent data safetymonitoring committee to be unrelated to the device itself. There were nomajor intra-operative complications. Specifically, we did not encounterorgan perforation or significant bleeding. Furthermore, we did notobserve post-operative intra-peritoneal infections, electrode migrationor tissue erosion.

Changes in cardiovascular parameters such as modest decreases in heartrate and blood pressure appear to be consistent with the weight lossitself and no deleterious effects on cardiovascular risk factors wereobserved. Although the current sample size is small, the apparent lackof undesirable effects on blood pressure and heart rate are important tonote since the vagus is a prominent regulator of parasympathetic tone onthe cardiovascular system at the thoracic level. The intermittent vagalblockade is applied at the sub-diaphragmatic level. Experimental animalstudies also show that there is no histological evidence of Walleriandegeneration or demyelination of the vagus after application of theelectrical algorithm in the pig for at least 55 days. (data not shown)Moreover, application of the electrical signal for inhibition of vagalfunction (5 kHz for 5 minutes) has been shown to be rapidly reversible;thus, within 5 minutes of cessation of the inhibition algorithm, thereis a recovery of >75% compound action potentials relative to baseline inboth Aδ and C fibers of the vagus nerve.

Vertical banded gastroplasty was performed either with (30 patients) orwithout (39 patients) truncal vagotomy on 69 morbidly obese patientswith a mean BMI of 47 kg/m², (Kral J G, Gortz L, Hermansson G, Wallin GS. Gastroplasty for obesity: Long-term weight loss improved by vagotomy.World J Surg 1993; 17:75-9.) In patients followed for one year orlonger, the vagotomy group had an average excess body weight loss (EWL)of 51% as compared to 34% for the non-vagotomy patients. In a separatelong-term series of 21 patients, however, it was observed that initialweight loss was not maintained. (Groetz L, Kral J B. A five- toeight-year follow-up study of truncal vagotomy as a treatment for morbidobesity. Proceedings, Third Annual Meeting, American Society forBariatric Surgery, Iowa City, Iowa, 18-20 Jun., 1986, p. 145) Theeffects of surgical vagotomy in preclinical studies in rodents suggestthat, while there is inhibition of gastric accommodation for two weeks,the latter function was restored after continuous vagal interruption forfour weeks. Takahashi T, Owyang C. Characterization of vagal pathwaysmediating gastric accommodation reflex in rats. J Physiol 1997;504:479-88. The precise mechanism of this adaptation is unclear.

Based on the findings from this clinical trial, it can be concluded thatintermittent, intra-abdominal vagal blocking using a novel, programmablemedical device is associated with both significant excess weight lossand a desirable safety profile. Furthermore, study data support thetherapeutic rationale of intermittent, intra-abdominal vagal blocking bydocumenting decreased hunger between meals and earlier satiation atmeals, as well as an association between weight loss and vagalinhibition. In addition, a subset of patients shows a significantreduction of HbA1c at 4 weeks post treatment, suggesting an increase inglycemic control. These positive clinical results have led to the designand implementation of a randomized, double-blind, prospective,multi-center trial.

With the foregoing detailed description of the present invention, it hasbeen shown how the objects of the invention have been attained in apreferred manner. Modifications and equivalents of disclosed conceptssuch as those which might readily occur to one skilled in the art areintended to be included in the scope of the claims which are appendedhereto. In addition, this disclosure contemplates application of acombination of electrical signal treatment by placement of electrodes onone or more nerves, one or more organs, and combinations thereof. Thisdisclosure contemplates application of a therapy program to downregulate neural activity by application of electrical signal treatmentby placement of electrodes on one or more nerves, one or more organs,and combinations thereof. This disclosure contemplates application of atherapy program to up regulate neural activity by application ofelectrical signal treatment by placement of electrodes on one or morenerves, one or more organs, and combinations thereof. This disclosurecontemplates application of one or more therapy programs to downregulate and/or upregulate neural activity by application of electricalsignal treatment by placement of electrodes on one or more nerves, oneor more organs, and combinations thereof.

In the sections of this application pertaining to teachings of the priorart, the specification from prior art patents is substantiallyreproduced for ease of understanding the embodiment of the presentinvention. For the purpose of the present application, the accuracy ofinformation in those patents is accepted without independentverification. Any publications referred to herein are herebyincorporated by reference.

What is claimed is:
 1. A system for treating a patient with impairedglucose regulation comprising: at least two electrodes operablyconnected to an implantable pulse generator, wherein one of theelectrodes is adapted to be placed on a vagus nerve below a vagalinnervation of the heart; an implantable pulse generator that comprisesa power module and a programmable therapy delivery module, wherein theprogrammable therapy delivery module is configured to deliver at leastone therapy program comprising an electrical signal treatment appliedintermittently multiple times in a day and over multiple days to thevagus nerve, wherein the electrical signal treatment is selected toreduce a HbA1C %, has a frequency selected to downregulate activity onthe vagus nerve of at least 500 Hz, an on time and an off time, whereinthe off time is selected to allow at least a partial recovery of theactivity of the vagus nerve; and an external component comprising anantenna and a programmable storage and communication module, whereinprogrammable storage and communication module is configured to store theat least one therapy program and to communicate the at least one therapyprogram to the implantable pulse generator.
 2. The system of claim 1,wherein the at least one electrode is adapted to be placed on an organselected from the spleen, stomach, duodenum, pancreas and ileum.
 3. Thesystem of claim 1, wherein the at least one electrode is adapted to beplaced on a second target nerve selected from a splanchnic nerve, ahepatic branch of the vagus nerve, a celiac branch of a vagus nerve andcombinations thereof.
 4. The system of claim 1, wherein the programmabletherapy delivery module is configured to deliver an electrical signalhaving a frequency of at least 500 to 5000 Hz.
 5. The system of claim 1,wherein the programmable therapy delivery module is configured todeliver an electrical signal having an on time of about 30 seconds to 5minutes.
 6. The system of claim 5, wherein the programmable therapydelivery module is configured to deliver an electrical signal having anoff time of about 5 to 30 minutes.
 7. The system of claim 1, wherein theprogrammable storage and communication module is configured to deliver atherapy program to the implantable pulse generator, wherein the programcomprises an electrical signal treatment applied intermittently multipletimes in a day and over multiple days, wherein the electrical signaltreatment is selected to reduce a HbA 1C %, has a frequency selected todown-regulate activity on the vagus nerve of at least 500 Hz, and has anon time and an off time, wherein the off time is selected to allow atleast a partial recovery of the activity of the vagus nerve.
 8. Thesystem of claim 1, wherein the programmable storage and communicationmodule is configured to store and communicate more than one therapyprogram, wherein each therapy program is different from one another, andis configured to be selected for communication.
 9. The system of claim1, wherein programmable therapy delivery module is configured to delivera second therapy program comprising an electrical signal treatmentapplied intermittently multiple times in a day and over multiple days toa second target nerve or organ, wherein the electrical signal has afrequency selected to upregulate or down-regulate activity on the secondtarget nerve or organ and has an on time and an off time, wherein theoff time is selected to allow at least a partial recovery of theactivity of the second target nerve or organ to baseline levels.
 10. Thesystem of claim 9, wherein the second target nerve is the splanchnicnerve or the celiac branch of the vagus nerve.
 11. The system of claim9, wherein the second target organ is the duodenum or ileum.
 12. Thesystem of claim 1, further comprising a sensor operable connected to theimplantable pulse generator.
 13. The system of claim 12, wherein thesensor detects an increase or decrease of blood glucose from a thresholdlevel.
 14. The system of claim 12, wherein the programmable therapydelivery module is configured to deliver the second therapy program inresponse to a signal from the sensor.
 15. The system of claim 9, whereinthe upregulating signal has a frequency of less than 200 Hz.
 16. Thesystem of claim 15, wherein the on time is about 30 seconds to 15minutes.
 17. The system of claim 15, wherein the off time is about 5 to45 minutes.
 18. A method of treating a condition associated withimpaired glucose regulation in a subject comprising: Treating thesubject by applying an intermittent electrical signal to a vagus nervebelow a vagal innervation of the heart of the subject having impairedglucose regulation using the system of claim 1, with said electricalsignal treatment selected to reduce a HbA1C %, and selected todown-regulate neural activity on the vagus nerve with a frequency of atleast 500 Hz, and to restore neural activity on the vagus nerve upondiscontinuance of said signal.
 19. The method according to claim 18,wherein the condition is type 2 diabetes.
 20. The method of claim 18,wherein the electrical signal is applied intermittently in a cycleincluding an on time of application of the signal followed by an offtime during which the signal is not applied to the nerve, wherein the onand off times are applied multiple times per day over multiple days. 21.The method of claim 20, wherein the on time is selected to have aduration of about 30 seconds up to about 5 minutes.
 22. The methodaccording to claim 18, wherein the electrical signal is applied at afrequency of about 500 Hz to 5000 Hz.
 23. The method according to claim18, wherein the electrical signal is applied on the hepatic branch ofthe vagus nerve.
 24. The method according to claim 18, wherein theelectrical signal is applied on the celiac branch of the vagus nerve.25. The method according to claim 18, wherein the electrical signal isapplied to the liver, duodenum, jejunum, ileum, or combinations thereof.26. The method of claim 18, further comprising applying an upregulatingsignal to a second target nerve or organ.
 27. The method of claim 26,wherein the downregulating and upregulating signals are applied at thesame time or different time.
 28. The method of claim 26, wherein thesecond target nerve is the splanchnic nerve.
 29. The method of claim 26,wherein the second target organ is the duodenum or ileum.
 30. The methodaccording to claim 18, further comprising administering an agent thatimproves glucose control.
 31. The method of claim 30, wherein the agentincreases the amount of insulin and/or increases the sensitivity ofcells to insulin.
 32. The method of claim 31, wherein the agent thatincreases the amount of insulin is selected from the group consisting ofinsulin, insulin analogs, sulfonylureas, meglitinides, GLP-1 analogs,and DPP4 inhibitors.
 33. The method of claim 31, wherein the agent thatincreases the sensitivity of cells to insulin is a PPAR alpha, gamma, ordelta agonist.
 34. A diabetes or prediabetes treatment comprising: i)selecting a drug for treating diabetes or impaired glucose control for apatient where effective dosages for treating diabetes or prediabetes forsuch a patient are associated with disagreeable side effects or impairedglycemic control; and ii) treating a patient for diabetes or impairedglucose control with a concurrent treatment comprising: a) applying anintermittent electrical signal treatment using a system of claim 1 to avagus nerve below a vagal innervation of the heart of the patient atmultiple times per day and over multiple days, wherein the electricalsignal treatment is selected to reduce a HbA1C %, and selected todown-regulate afferent and efferent neural activity on the vagus nervewith a frequency of at least 500 Hz, and with neural activity restoringupon discontinuance of said block; and b) administering said drug to thepatient.
 35. A method of making a system for treating a patient withimpaired glucose regulation comprising: providing at least twoelectrodes operably connectable to an implantable pulse generator,wherein one of the electrodes is adapted to be placed on a vagus nervebelow a vagal innervation of the heart; configuring a programmabletherapy delivery module of the implantable pulse generator to deliver atleast one therapy program comprising an electrical signal treatmentapplied intermittently multiple times in a day and over multiple days tothe vagus nerve, wherein the electrical signal treatment is selected toreduce a HbA1C %, has a frequency selected to downregulate activity onthe vagus nerve of at least 500 Hz, and has an on time and an off time,wherein the off time is selected to allow at least a partial recovery ofthe activity of the vagus nerve; and configuring a programmable storageand communication module of an external component to store the at leastone therapy program and to communicate the at least one therapy programto the implantable pulse generator.
 36. The method of claim 35, furthercomprising configuring the programmable therapy delivery module of theimplantable pulse generator to deliver the second therapy programcomprising an electrical signal treatment applied intermittentlymultiple times in a day and over multiple days to a second target nerveor organ, wherein the electrical signal has a frequency selected toupregulate or down-regulate activity on the second target nerve or organand has an on time and an off time, wherein the off time is selected toallow at least a partial recovery of the activity of the second targetnerve or organ to baseline levels.
 37. The method of claim 35, furthercomprising providing a sensor to the implantable pulse generator. 38.The method of claim 35, further comprising configuring the programmabletherapy delivery module of the implantable pulse generator to deliverthe second therapy program upon a signal from the sensor.